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CHAPTER 19

Skeletal muscle adaptability:


significance for metabolism and performance
August Krogh Institute, University of Copenhagen,
BENGT SALTIN
Copenhagen, Denmark
Department of Physical Education for Men, Washington
PHILIP D. GOLLNICK
State University, Pullman, Washington

CHAPTER CONTENTS Living systems are worn out by inactivity


and developed by use.
Motor Unit A. Szent-Gyorgyi
Fibers per motor unit
Contractile properties
Biochemical basis for differences in twitch properties SKELETAL MUSCLES ARE AGGREGATES of muscle fibers
Histochemical differentiation of muscle fibers that can be controlled individually or collectively. The
Ultrastructural basis for skeletal muscle fiber typing
Maximal contractile force multiplicity of movement patterns produced by man
Speed of contraction in daily life testifies to the intricate control that the
Fatigue characteristics nervous system has over the muscles and indicates the
Metabolic characteristics diverse characteristics of the muscle fibers. The same
Substrates muscle or muscle group can respond and adapt to the
Enzyme activities
Ionic composition of skeletal muscle need for either fine control, short intense effort, or
Summary prolonged activity, which reveals the plastic nature of
Muscle Fiber Composition in Human Skeletal Muscle this tissue.
Motor-Unit Recruitment The individual motor units that unite to form an
Adaptive Response in Skeletal Muscle
Muscle size
entire muscle have different characteristics. The adap-
Postnatal development tive responses seen in muscle may therefore depend
Use and disuse on a combination of the types of motor units contained
Hypertrophy versus hyperplasia in the muscle and the pattern or patterns of activity
Summary that they engage in. This chapter begins with a brief
Metabolic capacity
Postnatal development
description of the motor unit and the basis for classi-
Use and disuse fication by fiber type that is used throughout to enable
Regulation the reader to understand our approach to the subject
Connective Tissue of adaptations to use or disuse. The topic of motor
Capillaries unit properties has been reviewed in depth by Close
Methodology
Anatomy (122) and by Buchthal and Schmalbruch (91).
Capillary density
Growth and development
Muscle fiber types and potential for oxidative metabolism MOTOR UNIT
Capillary length and diameter
Use and disuse
Capillary density The awareness that skeletal muscle is composed of
Capillary length and diameter different fiber types is not new. Although it is difficult
Myoglobin to establish the first systematic description of these
Regulation
Significance of Adaptation
differences, it is frequently attributed to Ranvier (569).
Muscular size Major advances in identifying the properties and
Substrate stores organization of motor units within muscles came from
Enzyme activities the histochemical staining for glycogen in cross sec-
Anaerobic metabolism tions of muscle combined with isolating and stimulat-
Aerobic metabolism
Summary ing individual motoneurons repetitively (176). A loss
of glycogen identified those fibers (motor units) that
555
556 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

had been active. A number of characteristics of the fibers per motor unit is from 110 for the lumbricalis to
active fibers could then be identified from serial cross 1,720 for the gastrocnemius medius muscles (216). At
sections stained by histochemical methods. The initial present there are no exact determinations of the num-
studies were done with rats (176, 437, 439, 440), after ber of fibers in the different types of motor units found
which similar data were added from cat hindlimb in human skeletal muscle.
muscle (97, 99, 101, 102). Because of their invasive
nature, these methods cannot be applied directly to Contractile Properties
the study of motor unit properties in human skeletal
muscle. The basic feature that differentiates motor units
However, some motor-unit mapping of human skel- into types is their contractile properties. These are
etal muscle has been done with electrophysiological identified from the time to peak tension in a twitch
methods (237, 485, 486). Such studies have demon- and the closely related one-half relaxation time. Two
strated a remarkable degree of similarity in the organ- general classes of motor units and in some cases of
izational pattern from human and animal muscle. The complete muscles can be identified from these con-
general characteristics of the motor unit are enumer- tractile properties. One group of motor units possesses
ated. 1) All fibers in a single motor unit are homoge- a relatively long time to peak tension (a slow twitch)
neous with regard to histochemically identifiable con- and the other a short time to peak tension (a fast
tractile and metabolic properties (237, 437, 441). 2) twitch). Available data on the contractile properties
The fibers in a motor unit are distributed in a fairly of various motor units or muscle fibers within a single
large part of the cross-sectional area of the muscle muscle illustrate the existence of a clear dichotomy of
(10%-30% for the rat tibialis anterior muscle) (183).3) contractile speeds between fiber types (98-102, 223,
Fibers belonging to a single motor unit are rarely 437,438,540). A discrete dichotomy does not extend,
positioned immediately proximal to each other. 4) A however, to the individual motor units, where there is
central locus for a motor unit exists with the density a wide range of contractile speeds in spite of similar
of fibers in the unit declining as a function of the histochemical characteristics.
distance from the center (176,440). In the cat gastroc-
nemius muscle, fibers belonging to 40 or 50 motor Biochemical Basis for Differences in
units may be found in the same region (mm") of the Twitch Properties
muscle (101). In man, there appear to be only 15-30
motor units contained in a 5- to 1O-mm2 cross-sectional A prime determinant of the twitch property of mus-
area (86-88). Motor units found in a given area can cle is the rate at which myosin splits adenosine 5'-
belong to all of the types represented in the muscle. triphosphate (ATP), that is, its ATPase activity (31,
32,606,656). This is best illustrated when pure myosin
is activated by actin. With such an assay system the
Fibers per Motor Unit
specific activity of the pure protein is obtained without
Data are available on the number of fibers per motor the dilution effect produced by the presence of other
unit for a few muscles of several animals including contaminating proteins. The relationship between the
man. For some animal studies the glycogen-depletion specific ATPase activity of myosin and contractile
method was used to make these estimates. In others speed for a variety of muscles with varying twitch
the number of motoneurons entering the muscle along times is presented in Figure 1.
with estimates of the total fiber number were used to The differences in the specific ATPase activity of
calculate this ratio. In the rat soleus, containing a total myosin are attributable to the existence of multimo-
of about 2,500 fibers, there are approximately 35 motor lecular forms of the protein (76-78, 240, 242, 243, 351,
units (297). The range of fibers per motor unit in the 352,466,533). These polymorphic forms of myosin can
rat is from 50 to 178 with a mean of 125 (176,438). be identified and differentiated from a number of
The tibialis anterior muscle of the cat has been re- physicochemical characteristics. The simplest method
ported to contain 56,000 fibers (156). The range for the for identifying the myosin isozymes is based on their
slow-twitch (ST) motor units has been reported to be susceptibility to loss of ATPase activity in response to
from 469 to 1,323 fibers per motor unit with the changes in pH (77, 78). Myosin from FT muscles is
average being 775. For the fast-twitch (FT) motor alkaline stable but acid labile (Fig. 2). The opposite is
units the average was 169 fibers per motor unit with true for myosin from ST muscles.
a range of from 43 to 382 (156). In the studies of cat The multimolecular nature of myosin becomes a
skeletal muscle only a small percent of the total num- feature of all of the components that are assembled to
ber of motor units was examined. form the functional protein complex (64a). This com-
Data from man are quite difficult to obtain. The plex is composed of both a heavy- and a light-chain
most reliable estimates have come from counting the portion (463, 467, 655, 717). The heavy-chain portion
total number of motor nerves and muscle fibers (115, can be divided into the structural subunits of the rod
121, 216). Estimates based on electrophysiological and the head. The ATPase activity is localized in the
(485) measurements are less reliable. The range of head subunit of myosin. Proteins of low molecular
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 557

30
..,
.,o
~

Ul 25
)(

Ol

Q.
E
"120
.,
Ul
0
Q.
FIG. 1. Relationship between maximal speed of
shortening and actin-activated ATPase of myosin
I-
<l:
15
from a variety of animal species. Equation from
the regression line is y = 0.34 + 1.37 x, and for the
'"., 2 variables, r = 0.97. [Plotted from original data
-0 published by Barany (31).]

-
.-> 10
o
<l:

-
.-c:
o
<l:
5


0
J 5 10 15 20 25 30
Contractile Speed - Muscle Lengths z s ec

weight, the myosin light chains, are associated with the ST soleus muscle contains only the fourth and
the head portion of the heavy myosin. Identification fifth isozymes. In addition to isozymes of myosin, it
of the components of myosin can be made through the has also been demonstrated that other proteins of the
use of immunological methods used in conjunction myofibrillar complex exist in polymorphic forms (148-
with histochemistry (Fig. 3). With these methods spe- 151, 669). Table 1 summarizes the variations in the
cific antibodies have been prepared against all sub- proteins found in the contractile apparatus of skeletal
units of the heavy chain and the individual light muscle. In summary there are major differences be-
chains. Two classes of slow and three classes of fast tween the proteins of the myofibrils of the FT and the
ATP-splitting myosin have been identified with these ST muscles. On the basis of these differences the fibers
techniques (595, 596). In general each muscle fiber can be most reliably typed.
contains only one class of myosin (that is slow or fast) The present data suggest that under normal condi-
but the relative proportion of the different isozymes tions the assembly of the individual units of the myo-
in this class can vary. There are, however, instances in fibrillar proteins occurs in such a manner that a com-
which fibers may contain a mixture of classes of plete randomization of the subunits does not or only
myosin (421, 552, 715). These immunological methods rarely takes place. Thus it is unlikely that the light
hold great promise for positively establishing the ex- chains associated with the fast-type heavy myosin will
istence of a specific type of myosin in a given fiber and be assembled with the slow-type myosin. The general
the possible interconversion of fiber types in response observation that only one class of contractile protein
to experimental perturbations such as chronic use or is found in a single muscle fiber does not preclude the
disuse. existence of minor components of other types of pro-
Electrophoretic methods have also demonstrated teins. Examples, of this can be found in fetal and
the existence of different types of myosin in skeletal neonatal stages (240,476,595,716,718), during chronic
muscle (351, 352, 552, 715). With these methods five electrical stimulation (437, 438, 552, 596, 715), and
myosin isozymes have been identified in rat muscle, after cross innervation and reinnervation (33, 421,
which is like the findings with immunological methods. 475). The presence of more than one form of myosin
These isozymes result from varying combinations of in fetal and neonatal muscle is probably due to the
the light chains associated with the heavy chains. Of existence of polyinnervation, which disappears with
the five isozymes of myosin, the FT extensor digitorum maturation (81, 82, 525-527). Fast-twitch muscle fibers
longus muscle of the rat contains principally the first also possess a greater concentration of sarcoplasmic
four with only trace amounts of the fifth. In contrast reticulum (218), and it changes with development
558 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

White Vastus sections at pH 4.3, 4.6, and 10.3 (77). Preincubation of


2.5 (FGI muscle sections at pH 10.3 results in a loss of the
histochemically demonstrable stain for myofibrillar
o sedentary
ATPase in fibers that have a low specific ATPase
2.0 trained
activity of purified myosin. These fibers have ST
contractile properties. Conversely all classes of FT
1.5 fibers stain intensely after alkaline preincubation.
Preincubation of muscle sections at pH 4.3 results in
a loss of ATPase staining in a majority of the FT
1.0 fibers, whereas the ST fibers stain intensely. A prein-
cubation of the sections at pH 4.6 produces a subdi-
vision of the FT fibers. After such preincubation a
0.5 population of FT fibers, as identified by staining after
treatment at pH 10.3, exists that retains some ATPase
staining. Immunological methods have demonstrated
that these histochemical staining patterns produced
by manipulation of the preincubation pH are the result
of the presence of different myosin isozymes (239, 240,
242). This finding extends to the different classes of
FT fibers, including those with either high or low
oxidative capacities present in the limb muscle of most
animals (240). The staining pattern that exists in most
mammalian muscles in response to variation in the
pH of the preincubation is presented in Figure 3.
Engel (192, 193) proposed that the fibers be identi-
fied as type I and type II. Brooke and Kaiser (76-79)
have proposed a scheme for classifying fibers in skel-
etal muscle based on the different sensitivities of the
myofibrillar ATPase toward acid and alkaline inacti-
vation. Based on the differential staining pattern as
illustrated in Figure 4, the fibers have been designated
as type I or type II. The type I fibers are acid stable
and alkaline labile, whereas the converse is true for
the type II fibers. Type I fibers are found in ST muscle
and type II in FT muscle. The type II fibers are further
subdivided into IIA, lIB, and IIC based on their re-
o 6.0 7.0 8.0 9.0 10.0
sistance to loss of histochemically demonstrable myo-
fibrillar ATPase at the low pH values.
pH In this chapter classification of skeletal muscle fibers
2 is based on the histochemical differentiation of myo-
FIG. 2. Influence of pH on Ca + -activated ATPase activites of
myosin from white [fast-twitch, glycolytic (FG)] and red [fast- fibrillar ATPase (602, 642). The assumption being
twitch, oxidative, glycolytic (FOG)] portions of the vastus muscle made is that the acid stable and the alkaline stable
and soleus [slow-twitch, oxidative (SO)] muscle of the sedentary myofibrillar ATPase correspond to slow and fast con-
(0) and endurance-trained (e) rats. ATPase activities were deter- tractile characteristics, respectively. Justification for
mined at 25C. [From Watrus (713).]
using the myofibrillar ATPase staining pattern after
acid or alkaline preincubation as an indication for the
(152), electrical stimulation (323, 325), and cross in- contractile properties of the fibers comes from the
nervation (157, 654). finding that the ATPase activity of myosin purified
from either FT or ST muscle behaves similarly when
Histochemical Differentiation of Muscle Fibers exposed to acid or alkaline preincubation (33). More-
over a homology exists for the reaction of antibodies
The difference in the sensitivity of myosin for re- prepared from purified myosin or its subunits (includ-
taining or losing ATPase activity after exposure to ing rod, head, or light chains), with the FT or ST
either high or low pH is a reliable method for the fibers as identified from the histochemical methods
histochemical classification of muscle fibers (192,533). depending on the source of the original protein used
It is a simple, rapid, and inexpensive method for in antibody production (240). Hence the basic desig-
determining the fiber composition of whole muscle or nation of the fibers is ST or FT. The FT fibers are
portions of muscles. This histochemical method for further subdivided into FTa , FT b , and FTc on the basis
fiber identification is based on the ATPase activity of differences in myofibrillar ATPase stability to low
remaining in myofibrils after preincubation of serial pH (see Fig. 4). The choice of the ST and FT desig-
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 559

FIG. 3. A: rat diaphragm, serial


transverse sections. Left stained with
antibody specific for alkali 1 light
chain (anti-at); right stained with an-
tibody for alkali 2 light chain (anti-
~2). Both antibodies react with same
fibers (W, I, black R) that react with
antibodies against whole white my-
osin. However, level of response to
anti-~ is lower in fast-twitch red fi-
bers (black R) than in other fast-
twitch fibers (W, 1). B: cat flexor
digitorum longus, serial sections. Left,
anti-zrl: right, anti-az, Response of
most fast-twitch fibers (W) is weak;
compare with unreactive fibers
(white R). However, level of response
to anti-a! (left) is more intense in
one type ofred fibers (black R) than
in other fast-twitch fibers. Response
to anti-~2 is less intense in this fiber
(black R) than in other fast-twitch
fibers. [From Gauthier (240).]

nation is not the result of any objection to the type I FT fibers or ST fibers was based on a standard ATPase
and II designation. It is merely an attempt to give the stain (pH 10.3 preincubation) and a staining for oxi-
classification more physiological meaning. dative and glycolytic enzymes, and not on the basis of
This nomenclature is similar to that proposed by ATPase staining after a combination of alkaline and
Peter et al. (540) from the histochemical study of acid preincubations. In the skeletal muscle of seden-
guinea pig limb muscle. In this and most other animal tary man, differences in metabolic potential can be
species the subgroups of FT fibers are easily discerni- identified from both histochemical (Fig. 4) and bio-
ble on the basis of large differences in metabolic pro- chemical (see Tables 2 and 4) techniques when com-
files. This is most marked for the mitochondrial en- paring subgroups of FT fibers, but these are small and
zymes where one of the subgroups of FT fibers has a an overlap is present. When subgrouping of the fiber
high or higher oxidative potential than the ST fibers, types in human skeletal muscle is based on ATPase
whereas another is very low in oxidative enzymes. The stains after both alkaline and acid preincubations
FT fiber types were therefore designated fast-twitch, rather than stains for oxidative or glycolytic enzymes,
oxidative, glycolytic (FOG) or fast-twitch, glycolytic rather large differences are obtained in which fibers
(FG). Also the designation into the basic subgroups of can readily be assigned to the various groups (74-77).
560 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

TABLE 1. Distribution of Multimolecular Forms of The FT a fibers had Z bands of intermediate width and
Myofibrillar Proteins in Type I and Type II three strong and two weak (low-density) M-bridge
Fibers of Mammalian Skeletal Muscle lines. The FT b fibers had narrow Z bands and three
strong and two very weak M-bridge lines. A higher
Protein Type I Fiber Type II Fiber'
degree of accuracy for fiber identification existed from
Myosin Slow Al homodimer Fast Al homodimer examination of the M rather than the Z band (95% vs.
Slow Al A2 Fast Al A2 70%). The identification of ultrastructural differences
heterodimer heterodimer in skeletal muscle fibers supports the concept that the
Slow A2 homodimer Fast A2 homodimer
Actin a a basic constitution of a fiber lies in the contractile
Tropomyosin f3 f3 proteins.
Troponin C Slow Fast Other features commonly examined with electron
Troponin T Slow Fast microscopy are the size, shape, and concentration of
Troponin I Slow Fast
the mitochondria. Examination of mitochondria is
'Note that data of Gauthier and Lowey (242) suggest that based on the assumption that ST muscle possesses
differences exist in distribution of isomeric form of myofibrillar
proteins, which could account for the presence of subpopulations of
higher oxidative capacity and therefore a higher con-
type II fibers. [Adapted from Dhoot and Perry (151).] centration of mitochondria than FT muscle. This re-
lationship between mitochondrial concentration and
contractile characteristics is not valid for FT muscles
Moreover this system eliminates the uncertainty that that possess high mitochondrial concentrations (240,
arises when changes in the oxidative potential occur 540, 696). Moreover the mitochondrial content of skel-
in response to altered patterns of chronic physical etal muscle is markedly influenced by the amount and
activity. Thus with extensive endurance training all type of activity of that muscle. Thus an examination
fiber types in the trained muscle may stain similarly of mitochondrial features holds little promise as a
for oxidative capacity, thereby making identification reliable method for fiber identification.
of fiber types based on this characteristic difficult if
not impossible. Therefore it may be wrong to include Maximal Contractile Force
abbreviations for the metabolic profile in the names
to identify fibers as these, at least for man, can be Considerable interest exists in identifying the factor
misleading. The subscripts a, b, and c that we prefer or factors that contribute to the capacity of skeletal
to use indicate that there are certain differences in the muscle to develop tension. A plethora of reports de-
populations of FT fibers. Whether they are related to scribe muscular strength increases in response to
differences in the myosin isozymes, energy metabo- heavy-resistance exercise and decreases after inactiv-
lism, or other features of the muscle fiber cannot ity. An interesting aspect of this topic is the question
presently be evaluated. The studies of Gauthier and of whether any changes occur in the contractile prop-
Lowey (240, 242, 243) do suggest that differences in erties of the fibers themselves in response to different
the isozymes of the contractile proteins exist for the patterns of physical activity. The central issue is
FT muscle of the rat. whether changes occur at the level of the individual
fiber. The capacity of a muscle or fiber to develop
Ultrastructural Basis for Skeletal Muscle force is best related to the tension produced per unit
Fiber Typing of cross-sectional area (427). The isometric tension
developed by single, skinned, human muscle fibers in
Attempts have been made to identify the fiber types response to ionized Ca2+ has been reported to be about
in skeletal muscle by ultrastructural features detecta- 15 Nzcm" (726). Ikai and Fukunaga (381, 382) exam-
ble by electron microscopy (238, 241, 538, 696). The ined this relationship in man by determining both the
width of the Z band has been reported to vary in a maximal voluntary contractile strength (MVC) and
systematic manner in the different fibers of some the cross-sectional area of the arm flexor muscle in
animals (238, 241, 696). In early studies with the rat a children and adults. Cross-sectional area of the mus-
fairly consistent pattern exists of a wider Z band in cles was estimated from ultrasound echoes; MVC was
the ST fibers (238, 241). In more recent studies this estimated to be 6.4 kg/ern" (64 N/cm2 ) with no differ-
relationship is less clear (239). A similar pattern has ences between male and female subjects.
not been demonstrated in human skeletal muscle, The maximal' voluntary force as reported by Ikai
however, nor has it been possible to identify the sub- and Fukunaga (381, 382) is an overestimate of the true
types of FT muscle based on this criterion. Sjostrom capacity of human skeletal muscle. The total muscle
and co-workers (643) have examined the ultrastruc- mass involved in elbow flexion includes the pronator
tural features of the Z and M bands of human skeletal teres, extensor carpi radialis longus, and brachioradi-
muscle (Fig. 5). The fibers were identified by histo- alis muscles (66, 69). Moreover the placement of the
chemical staining for myofibrillar ATPase prior to origin and insertion of the biceps brachii muscle on
electron microscopy. The ST fibers had wide Z and M the skeleton is such that in the position of elbow
bands with five strong (high-density) M-bridge lines. flexion used by Ikai and Fukunaga there is a 1: 4.9
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 561

FIG. 4. Serial transverse-sectioned frozen skeletal muscle from the lateral head of the gastrocne-
mius muscle of man (A) and the same muscle from rat (B). From top to bottom are the following
stains (myofibrillar ATPase stained at pH 9.4 and preincubated at pH 10.3,4.6,4.3): nicotinamide
adenine dinucleotide, reduced-tetrazolium reductase (NADH); a-GPDH, glycogen (periodic
acid-Schiff, PAS); capillaries (man = amylase-treated sections stained with PAS; rat = alkaline
phosphatase); and hematoxylin-eosin.
562 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

TYPE 1

... .
. . .. .
. . ..

TYPE2A

.
. .. . .

. .
. ... .
.
TYPE2B
MYOSIN z

.
.. .
M-BAND
A-BAND
SARCOMERE

FIG. 5. Part of a sarcomere from slow-twitch, ST (micrograph and top panel), fast-twitch, subtype
a, FT. (middle panel), and fast-twitch, subtype b, FT b (bottom panel) fibers in combination with a
schematic drawing of the respective fiber types. [From Angquist (9).]
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 563

mechanical advantage (309, 721). On the basis of these existence of a difference in force-generating capacity
factors the value given by Ikai and Fukunaga can be of ST and FT fibers (155).
calculated to be about 47 Nzcm". This is similar to a
value of 40 Nzcm'' reported for the biceps brachii by Speed of Contraction
Nygaard (520) and 39 N/cm2 as determined for the
calf muscles by Haxton (314). The speed of contraction, that is, the time to peak
The cross-sectional area of the upper arm flexors isometric tension, of individual motor units has been
and knee extensors of man has also been estimated studied most extensively in cat and rat skeletal muscle
from X-ray computerized tomography (100,384,578). (33, 35, 84, 98-101, 120, 121, 217, 223, 437, 438, 489).
In two of these studies (100, 578) the fiber composition For the rat the mean time to peak isometric tension is
of the muscles was estimated from biopsy samples. 13 ms and 38 ms for the FT and ST motor units,
This revealed that the maximal voluntary strength of respectively (33, 120, 121,217,437,438). In the cat the
human skeletal muscle is related to fiber composition values for FT units in the gastrocnemius muscle range
in only a minor way. Instead total cross-sectional area from 32 to 43 ms (99-101). The ST motor units in the
appeared to be the decisive factor. cat soleus muscle range from 77 to 97 ms (98). In the
The ability of the different types of muscle and guinea pig these values are 82 ms for ST muscle and
motor units to produce maximal tetanic tension has 21 ms for FT muscle (35).
been examined in the mouse, rat, and cat. Maximal As described earlier, a close relationship exists be-
tensions ranging from 15.7 to 21.5 N/cm 2 have been tween the contractile speed of a muscle and the spe-
reported for the soleus muscle of the mouse (592). For cific activity of its myosin. There is, however, consid-
the rat soleus and extensor digitorum longus muscles erable variation around the mean value for the con-
maximal tetanic tensions ranged from 19 to 21 and tractile times of motor units, more than that which
from 20 to 30 N/cm2 , respectively (33, 119, 120, 122, could be expected from differences in the staining
124). Sexton and co-workers (626, 627) reported that intensity for myofibrillar ATPase. Differences in the
there was no difference in force development between isozyme composition of myosin do exist in the different
ST and FT muscles in maximally activated, glycerol- motor units, such as between the different types of FT
extracted fibers. Independent measurements of the fibers (239, 240, 242, 243), however, and these may
maximal tetanic force developed by the cat soleus and contribute to the variation in contractile speeds.
extensor digitorum longus (215) muscles support the Other elements in the excitation-contraction cou-
concept that the intrinsic capacity of the contractile pling system may also exert a regulatory influence on
elements to develop tension is similar for ST and FT maximal speed of contraction of the individual motor
muscle. Burke and co-workers (97, 101), however, re- units. Included are properties of the nerve and motor
ported the maximal tetanic tension of FT motor units end plate, interneuronal modulations, characteristics
in cat muscle to be between 15 and 29 N / ern? as of the sarcolemma and transverse-tubular system for
compared to 6 Nzcm" for ST motor units. This differ- transmission of the neural impulse, the sarcoplasmic
ence could be due to the technical difficulties in ac- reticulum and its abilty to release and sequester cal-
curately assessing the cross-sectional area of the motor cium, and finally, the role of the isozymes of troponin
units that were stimulated. If such large differences in and tropomyosin in binding calcium and initiating
force-developing capacity do exist between ST and FT contraction. Very little is known regarding these other
motor units, its molecular basis is obscure. Differences regulatory factors.
could exist in excitation-contraction coupling, which Studies with man have lacked the precision for
ultimately involves the control of free calcium by the establishing contractile properties of the individual
sarcoplasmic reticulum. Further studies into this prob- muscle or motor units of those from animals. In situ
lem are needed. One preparation that may prove useful stimulation of motor units has demonstrated the ex-
for studies is the skinned muscle fiber. With this istence of FT and ST motor units (85, 89, 90, 94, 143-
preparation activation of the contractile process can 147,237,293,294,485,600). Thus in the biceps muscle,
be initiated without involvement of the sarcolemma or bimodal distributions of contraction times with maxi-
sarcoplasmic reticulum. Moreover exact assessments mal values of 36 ms and 90 ms were observed,
of the cross-sectional area of the individual fibers can whereas in the medial head of the gastrocnemius mus-
be made so that force development per square centi- cle the respective peak times were slightly longer.
meter is accurately determined. These data, combined This does not necessarily signify that differences exist
with assessments of the isozyme composition of the in contraction times between similar fiber types of
fibers being tested, should clarify the issue of whether these two muscles since the methods for recording
or not intrinsic differences in the capacity to develop tensions were different in the two studies. The longer
tension exist between the types of muscle and whether contraction times were observed in experiments where
this is related to the polymorphic forms of myosin or the torque of the whole ankle joint was measured,
the other proteins in the contractile elements. Data probably causing an elongation of the real time to
from these methods do not appear to support the peak isometric tension due to the inertia in the system.
564 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

In both studies the variation around the mean values a total of 57 single motor units of the medial gastroc-
for time to peak tension was large, especially for the nemius muscle were activated with a bipolar stimulat-
faster contraction times. There are also reports of ing electrode (Fig. 7). An electromyogram (EMG) of
contractile properties of biopsy samples of human a single motor unit was recorded, and tension pro-
skeletal muscle (162, 163, 181, 504). These support the duced by activation of a motor unit was estimated
existence of FT and ST motor units. The exact times from the torque produced in the ankle joint. As was
for attainment of peak tension as reported in such true for cat muscle, some motor units were more
studies, although they do not differ markedly from the resistant to fatigue than others. The slowest contract-
values cited above, are open to question since the ing motor units demonstrated a small decline (2%-
fibers had been cut and the integrity of the excitation- 20%) in twitch tension from the initial level after 3,000
contraction coupling system compromised. However, stimuli delivered over a 50-min period. Two groups of
membrane potential was maintained at near normal FT fibers were discernible. One had fatigue-resistance
levels in these cut but ligated muscle bundles. In these properties similar to the ST fibers, and the other had
preparations one-half relaxation times were also estab- a reduction in tension from 50% to 75% during the
lished and found to be approximately four times same experiment period.
shorter in FT than in ST fibers (179, 504,720). When
measurements were performed in intact man, assum- Metabolic Characteristics
ing a selective recruitment of ST fibers at low static
contraction and that all fibers engaged in maximal SUBSTRATES. Human skeletal muscle contains stores
contractions only twice as fast, a relaxation rate was of glycogen and lipids in addition to the more imme-
estimated for the ST as compared to the FT fibers diate energy sources of ATP and creatine phosphate
(504). (CP). A summary giving the average values for these
stores as compiled from several studies where they
Fatigue Characteristics were estimated from biopsy samples (see ref. 49) of
the extremity muscles is presented in Table 2.
Burke and co-workers (96, 98-100, 102) have exam- Triglyceride content. The triglyceride content of
ined the response of individual motor units of cat human skeletal muscle varies between 5 and 15 mmol/
muscle to contractile activity (Fig. 6). In these studies kg wet wt (197, 198,200,203,233,234). Although these
individual motor units were stimulated through the values are from measurements made on samples of
motoneuron and the tension development and fatigue mixed-fiber muscle freed from visible fat, the possibil-
characteristics determined. Three types of fast motor ity remains that part of this fat is localized in the
units were discernible in the medial gastrocnemius extrafiber space. However, since bundles of fibers,
muscle and one slow unit in the soleus muscle of the carefully liberated from freeze-dried muscle samples,
cat. All fast-twitch units produced high tetanic ten- contain similar amounts of triglyceride as those given
sion. One type of these fast-twitch units fatigued rap- in Table 2, the extrafiber lipid store does not appear
idly and was designated as fast twitch, easily fatigued to have been appreciable.
(FF). A second type was fatigue resistant (FR), and a The magnitude of the variation in the triglyceride
third was intermediate to the FF and FR and was stores between various muscles of the body is un-
identified as F(int). All motor units of the soleus known. Measurements made on biopsy samples of
muscle produced low tension and were resistant to muscles from the leg and arm suggest that the varia-
fatigue. They were designated simply as slow twitch tion is small. The localization of fat within the muscle
(S). Histochemical examination ofthe muscle revealed appears to be heterogeneous. When determinations
that the FT and ST motor units show patterns of were made on small samples (5-10 mg wet wt) the
staining for myofibrillar ATPase typical for the re- high values were three- to five-fold higher than the
spective muscles. lowest value found in 30- to 50-mg pieces of the same
It has been suggested that the fast-twitch motor muscle. Ultrastructural evaluations support the con-
unit with intermediate fatigue characteristics, F(int), cept that fat is localized in small droplets at varying
is the result of differences in the activity level of the intervals in a fiber. An additional factor contributing
cats. Thus cats that were allowed freedom to exercise to the variation of the triglyceride content in skeletal
had higher percentages of such motor units than cats muscle is the distinct difference in the lipid content of
maintained in cages. Considerable variation existed in the individual fibers with the STfibers containing
fatigue properties (within each group of fibers). This three to five times higher levels than the FT fibers
continuum of resistance to fatigue was probably asso- (202). Therefore differences in the lipid content must
ciated with the normal state of fiber use in these cats be expected when variation exists in the fiber compo-
during daily life. Resistance to fatigue was closely sition of the tissue samples being analyzed.
related to the activities of the oxidative enzymes as Differences in the lipid content of the fiber types
demonstrated by the staining intensity for succinate can be demonstrated when sections are stained with
dehydrogenase. This is similar to the findings in the either Sudan black or oil red 0 (454). With these
rat (176,437,441). treatments the ST fibers stain more intensely than the
A similar classification of human skeletal muscle FT fibers (89, 90). Since mitochondrial membrane
motor units has been made (237). In these experiments contains large amounts of lipid, which is also stained
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 565

Motor Umt Type FF FR S


Histochemical FG FOG SO
Profile

FIG. 6. Important features of organization of


motor units in medial gastrocnemius muscle of cat.
Diameters of muscle fibers and unit mechanical
responses are scaled appropriately for respective
groups, representing typical observations. Shading
in muscle fiber outlines denotes relative staining
intensities found for each histochemical reaction
(identified in the FF unit fibers). Note differences
in pattern as well as intensity of staining in the
oxidative enzyme reaction (3rd fiber from left in
each unit sequence). Note also the somewhat
smaller motoneuron innervating type S unit and
relation between number of group Ia synapses and
cell size; a low density of terminals (as in the FF
50 unit) produces a relatively small Ia excitatory post-
synaptic potential (EPSP), whereas increasing
40 densities (in the FR and higher still in the type S
unit) produce larger EPSPs. Motor unit type no-
30 menclature: FF, fast twitch, fatiguable; FR, fast
twitch, fatigue resistant; S, slow twitch. Histochem-
20 ical profiles: FG, fast twitch, glycolytic; FOG, fast
10 twitch, oxidative, glycolytic; SO, slow twitch, oxi-
dative. These 2 systems are essentially inter-
o -=----::=-=-==-==~-
I
changeable. [From Burke and Edgerton (97).]
100 msec o 100 200 msec

o
f-=4~-::llli\J.iilil\~0~ _
o 2 4 6 2 4 660024660
min min min

8 c o

[~[~

[~[ lLL
~ ~1dOlL
*' -
[~[~[
50

L.--...J ~
o 3000
100 msec 200 msec
FIG. 7. Examples of the 3 motor unit types found in human medial gastrocnemius. A, isometric
twitch; B, isometric tetanus 10 pulses/s; C, isometric tetanus 20 pulses/s; and D, fatigue test, control
and after 3,000 stimuli, expressed as a percentage of initial isometric tension. [From Garnett et al.
(237).]
566 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

TABLE 2. Human Skeletal Muscle Substrate in Vastus Lateralis Muscle


Fiber Types, JLffiol/g wet wt
Mixed Muscle,
Substrate
umol/g wet wt
ST FT FT.
Triglyceride 9.9 0.6 7.1 1.7 4.2 1.2
Glycogen 83.8 18 77.8 18 84.7 19 83.1 18 89.2 21
(glucose units)
ATP 5.0 0.2 4.9 0.1 5.1 0.2 5.3 0.2 4.9 0.1
CP 10.7 + 0.6 12.6 0.2 14.7 1.4 14.5 1.1 14.8 1.6
ST, slow twitch; FT, fast twitch; FT., fast twitch, a type; FT b , fast twitch, b type; ATP, adenosine triphosphate; CP, creatine phosphate.
Values are means 1 SD and are given for triglycerides in mixed muscles from refs. 197, 198,200,269,396; glycogen from refs. 197, 198,262,
263,267,341,373; ATP and CP from refs. 374, 415, 418, 428. Corresponding values on fiber types are from refs. 202 (triglycerides); 199,
201-203 (glycogen); 312, 375 (ATP and CPl.

by Sudan black or oil red 0, caution must be exercised FT fiber types (199, 201-203). The reason for this
in the interpretation of the histochemical staining variation is unknown, but it may be due in part to the
method to estimate the triglyceride stores of the in- technical difficulties of separating the fiber from the
dividual fibers. Consequently this method seems to support tissue and of accurately weighing the small
hold little promise for evaluating differences in lipid tissue fragments. Thus although a close relationship
stores of the different fiber types or in estimating has been demonstrated between the histochemical
changes induced by either exercise, diet, or training. evaluation of the glycogen content of muscle and the
Glycogen content. The average glycogen content value determined biochemically, it is surprising that
(Table 2) of human extremity muscle lies in the range these differences are not more evident in tissue stained
of from 50 to 90 mmol/kg wet wt. (All glycogen con- by standard histochemical methods.
centrations given as millimoles of glycosyl units.) Part Phosphagen. The phosphagen stores of skeletal
of this rather wide variation appears to be related muscle constitute 23-25 mmol/kg wet wt with the CP
to the diet and state of physical activity of the subject concentration being 18-20 and the ATP 4-5 mmol/kg
(51, 271, 373). Overall the glycogen granules are ho- wet wt [Table 2; (374,418,428)]. Variations between
mogeneously distributed throughout the muscle fibers muscles are small. The magnitude of the variation of
with only small differences existing in the glycogen these stores in the major fiber types of human muscle
content of ST and FT fibers or in the subgroups of FT has been examined (312,375). This has demonstrated
fibers of man (191, 201-203). Moreover only minor a slightly higher ATP and CP concentration in ST
variation in muscle glycogen is found when determi- fibers. These differences, however, are so small, 0.05
nations are made on multiple samples from the same mmol/kg wet wt for ATP and 1-3 mmol/kg wet wt for
muscle or when assays performed on small samples CP, as to be physiologically unimportant. Measure-
are compared with those made on larger samples from ments performed on samples with large differences in
the same muscle (373). fiber composition also have failed to demonstrate any
The glycogen content of the gastrocnemius, the major differences in the concentrations of the high-
quadriceps femoris, the triceps brachii, and the biceps energy phosphates (375).
brachii muscles of man all lie within the range of 50- The ATP and CP concentrations in mixed-fiber
90 mmol/kg wet wt (373, 641). Quantitative determi- muscle of nonhuman species (primarily the rat) are
nations of the glycogen content of the individual fiber similar to those observed in human skeletal muscle
types present in the vastus lateralis of the quadriceps (Table 3). In spite of this, significant differences do
muscle have revealed that at a glycogen concentration exist in the concentrations of ATP and CP in the slow-
of about 75 mmol/kg wet wt (:::::300 mmol/kg dry wt) and fast-twitch muscles, with the ATP content of FT
there is a 10-15 mmol/kg wet wt mean difference muscle being about 60% higher than that of the ST
between the ST and FT fibers with the latter fibers fibers and the CP content being from 70% to 100%
having the higher glycogen content (201-203). It ap- higher (375).
pears that for the subgroups of the FT fibers;' the FT b The glycogen and triglyceride (Table 3) stores of rat
fibers may contain more glycogen than the FTa fibers. muscle and other species are generally present at lower
These differences in glycogen content of the muscle concentrations than that obtained in mixed muscle of
fibers can be detected with periodic acid-Schiff (PAS) man. Thus the triglyceride and glycogen concentra-
stain, but at a glycogen content of 80-100 mmol/kg tions of rat skeletal muscle are only 25%-33% and
wet wt or above, the staining intensity is homogeneous 33%-50%, respectively, of that found in human skeletal
and neither subjective ratings nor spectrophotometric muscle. For glycogen, a similar pattern of distribution
methods can detect differences between fibers or fiber between fiber types appears to exist in most species,
types (171, 559). The variation in the glycogen content with the lowest concentrations being found in the ST
within a single fiber type has been reported to be from muscle and only minor differences existing between
about 50 to 650 mmol/kg dry wt for both the ST and the different types of FT muscles. In contrast, the red
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 567

portion of the vastus muscle in the rat, an FT muscle, to 100%was0.48{LmoIP j . m g - 1.min- 1 (203). This value
contains the higher triglyceride content, with similar is only slightly less than the 0.59 {Lmol Pi-mg v-min"
amounts being found in the ST soleus and FT white reported by Barany (31) for the biceps brachii muscle,
portion of the vastus muscle. In the guinea pig the a mixed-fiber muscle. The differences between the
triglyceride content is highest in the ST soleus, lowest activities reported in these studies appear to be the
in the FT oxidative red vastus, and intermediate in result of a better purification of the protein by Barany
the FT glycolytic white vastus (219). (31) made possible by the availability of a larger tissue
sample.
ENZYME ACTIVITIES. The content and/or activities of Some representative data about the ATPase activ-
enzymes for contraction and energy metabolism differ ity of myosin prepared from both ST and FT rat
in the various fiber types of skeletal muscle. This can skeletal muscle are presented in Figure 8. The ATPase
be demonstrated in a variety of nonhuman species activities were activated by Ca 2 +, K+, or actin. Of
when quantitative biochemical assays are performed these activators, actin clearly is better for differentiat-
on portions of muscles or whole muscles that contain ing the myosin from ST as compared to FT muscle.
only one fiber type (15). For man, in whom most The approximately threefold difference in the actin-
muscles are homogeneous mixtures of the different activated ATPase that exists between the myosin pre-
types, quantitative data are more difficult to obtain, pared from the soleus or from white portion of the
and results at the individual fiber level are scarce. It gastrocnemius or vastus muscles corresponds closely
has been possible, with the method developed by to the differences in the time to peak isometric tension
Essen, Saltin, et al. (203), to tease apart fragments of that have been reported for ST and FT muscle of the
single fibers from freeze-dried muscle samples and to rat (713). Estimations of the Michaelis constants (Km )
histochemically identify them according to type. The for the different types of myosin demonstrated that
remaining portion is then weighed on a quartz balance the affinity of myosin for actin was only about one-
and microchemical methods are applied. fourth as great for myosin from slow-twitch as com-
The Ca 2+ -activated myosin ATPase determined on pared to that from fast-twitch muscles (Fig. 9).
pooled samples of a single fiber type was 2.5-fold Creatine kinase. Major differences in creatine ki-
higher in the FT than ST fibers (203). The absolute nase activity of the fiber types appear to exist in all
values in these studies were somewhat low due to a skeletal muscle. For example, in human muscle the
loss of activity that occurred during the process of average creatine kinase activity has been reported to
freeze-drying and isolating the individual fibers. To be about 222 and 333 {Lmol.mg-1.min- 1for the ST and
estimate the absolute values, samples containing 100% FT fibers, respectively (686, 689, 690). When the FT
ST fibers were obtained from soleus muscle and from fibers are further identified as either FTa or FT b , the
other muscles that contained increasing percentages FT b fibers appear to have slightly higher activities
of FT fibers. The myosin ATPase activity of the ST than the FTa fibers. In the rat the creatine kinase
fibers averaged 0.16 {Lmol Pi-mg v-rnin", and the activity for the FT rectus femoris muscle has been
value obtained by extrapolating the FT fiber content reported to be 424 {Lmol.mg-1.min- 1 as compared to

TABLE 3. Summary of Substrate Level in Rat Heart and Various Fiber Types in Rat Muscles
Fiber Type, I'ffiol/g wet wt
Heart,
Substrate
I'mol/g wet wt
SO FOG FG
Triglyceride
Mean 1.35 2.13 2.45 1.95
Range 0.53-1.79 1.35-3.10 2.02-3.08 1.52-2.45
(231, 282, 576) (230-232,235,282,576)
Glycogen (glucose units)
Mean 27.5 30.3 40.8 42.6
Range 24.4-31.2 20.7-37.8 21.7-58.2 24.8-56.1
(27.282,469,576,679) (25,27,36,126,282,346,469,488,572,
576,577,581,608,625,676,679)
ATP
Mean 4.03 4.54 6.20 6.28
Range 3.6-4.31 3.9-5.8 5.8-6.5 6.1-6.4
(375,576)* (375,576)*
Creatine phosphate
Mean 4.6 11.65 16.8 18.14
Range 4.1-4.9 9.1-12.4 13.4-18.2 16.8-20.4
(375,576)* (375,576)*
so, slow-twitch, oxidative type from soleus; FOG, fast-twitch, oxidative, glycolytic type from red vastus lateralis; FG, fast-twitch,
glycolytic type from white vastus lateralis or psoas. Numbers in parentheses are references. * Unpublished data by P. D. Gollnick, G.
A. Klug, and L.-J. Cartier are also included.
568 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

o sedentary has been further quantified from biochemical studies


where enzyme activities for carbohydrate and fat me-
2.5 Ca++-activated
EZI trained
tabolism were determined at the level of the individual
muscle fiber (198, 203, 347, 468, 515, 554). In some
cases the fiber types were not histochemically iden-
tifed. Instead, the activities of several enzymes were
measured on each fiber and of these, lactate dehy-
drogenase (LDH) activity was used to type the fibers
(347, 468, 469). The results of these studies are sum-
marized together with values for mixed-fiber muscles
in Table 4. Glycolytic and mitochondrial enzymes are
quite consistent, that is, mitochondrial enzymes are
higher in ST than in FT fibers, and the reverse is true
for the glycolytic enzymes. An overlap is almost non-
existent. For all four glycolytic enzyme studies there
is a twofold-higher mean value in the FT than in ST
2.0
,.
c:
fibers. The subgroups of FT fibers also differ, with
activities being 20%-50% higher in the FT b than in
1.5 FTa fibers.
E The activities of 3-hydroxyacyl-CoA dehydrogenase
Cl 1.0
(HAD), succinate dehydrogenase (SDH), and citrate
E synthase (CS) are 30% to 50% higher in the ST than
in the FT fiber groups. When comparisons are made
ci...- 0.5
between FTa and ST fibers of the vastus lateralis
0 muscle, however, the difference for CS is small or
E 0 nonexistent. In contrast, HAD and SDH activities are
:::I.
20% and 30% lower in the FTa than in ST fibers. In
the study by Lowry et al. (468) of the biceps brachii
0.8 Actin-activated
muscle, CS activity was about 20% lower in the FTa
than in ST fibers. The activity of these enzymes in the
0.6 FTa fibers was approximately 50% of that found in the
ST fibers and 50%-67% that of the activity in FT b
0.4 fibers. Unfortunately no data are available for human
skeletal muscle for the activities of any respiratory
chain enzymes at the individual fiber level.
0.2 In samples of muscle containing a mixture of fiber
types the activity of the mitochondrial enzymes ap-
0 pears to be about 6-10 umol-rng v-min". In this case
Ht so FOG FG little difference exists between activities for the three
2+
FIG. 8. Ca -activated, K+-activated, and actin-activated ATP- major oxidative pathways (fatty acid oxidation, citric
ase activities of myosin from heart, soleus, red vastus, and white acid cycle, or electron-transport system). A constant
vastus muscles of sedentary and trained rats. Temperature, 37C; porportionality exists among mitochondrial enzymes
pH 7.4. Vertical lines, SEM. * Sedentary vs. trained, P < 0.05. Ht, (549).
heart; SO, slow-twitch, oxidative type from soleus; FOG, fast-twitch,
oxidative, glycolytic type from red vastus lateralis; FG, fast-twitch, The activities of the glycolytic enzymes are gener-
glycolytic type from white vastus lateralis. [Adapted from Watrus ally higher than those for the end-terminal oxidation.
(713).] In this pathway the enzymes also appear to be present
in a constant proportion to one another (543, 546-548).
114 p.ffiol.mg-1.min- 1 for the ST soleus muscle (659). No obvious deviation from this rule appears to exist
Histochemical staining of human skeletal muscle when comparisons are made at the individual fiber
has demonstrated the existence of major differences level.
in the metabolic profiles of the ST and FT fibers (see Data recording the activities of a wide array of
Fig. 2). The general pattern is for the ST fibers to be enzymes in the metabolic pathways of skeletal muscle
well endowed with enzymes for end-terminal oxidation from several nonhuman species are shown in Table 5.
and a low anaerobic potential, with the reverse being Only those for the laboratory rat are discussed because
true for the FT fibers. There is not, however, a discrete this is perhaps the most studied of the nonhuman
relationship, and enzyme activities vary considerably animals with regard to adaptive responses to varying
within each of the fiber types. Some insight into this patterns of physical activity. The general picture that
diversity within a given fiber type can be achieved emerges for rat tissue is that ST muscle, such as the
from the varying staining intensities of the fibers. It soleus muscle, possesses a low potential for glycolytic
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 569

D sedentary
o trained

1.50 Vmax 0.24


Km

1.25 0.20

--
I
c: 1.00 .....E
01
0.16
E E
0.12

-
01 0.75 ~

E c:
u
LL- 0.50 .s, 0.08
0

[ 0.25 0.04

0 0
FG FOG SO FG FOG SO
FIG. 9. Predicted Vm ax and apparent K m of actin-activated ATPase activity of myosin from white
vastus, red vastus, and soleus muscles of sedentary and trained rats. Vertical lines, SEM. FG, fast-
twitch, glycolytic type from white vastus; FOG, fast-twitch, oxidative, glycolytic from red vastus; SO,
slow-twitch, oxidative type from soleus. [Adapted from Watrus (713).]

TABLE 4. Enzyme Activities in Human Skeletal Muscle (Vastus Lateralis) for Carbohydrate and Fat
Metabolism Determined on Whole Muscle and on Fiber Types
Fiber Types, pmo[.g-l.min- 1
Mixed Muscle,
Enzyme pmo!.g-l.min- 1 Ref.
ST FT FT" FT h

Phosphorylase 6-7 2.8 7.3 5.8 8.8 202


Phosphofructokinase 20-25 7.5 15.4 13.7 17.5 203
6.2 11.9 202
Lactate dehydrogenase 107-210 59 257 221 293 202
94 16 195 12 179 18 211 3 347,468,469
Triosephosphate- 1341O 92 3 175 19 158 9 191 29 347,468,469
dehydrogenase
3-Hydroxyacyl-CoA 6.2-12.0 14.8 9.3 11.6 7.1 202
dehydrogenase 6.2 0.2 3.4 0.4 3.7 0.2 3.1 0.6 347,468,469
Succinate dehydrogenase 5.6-8.0 7.1 4.6 4.8 2.5 202, 203
Citrate synthase 6.0-11.5 10.8 7.5 8.6 6.5 202, 203
Activities are measured at 25C.

TABLE 5. Enzyme Activities for Fat and activity as indicated by the low activities of the key
Carbohydrate Metabolism in Rat Skeletal Muscle enzymes of phosphorylase (PHOS) and phosphofruc-
tokinase (PFK). Conversely this type of muscle (SO
Enzyme SO FOG FG Ref.
fibers) contains a rich supply of oxidative enzymes.
pmo!.g-l.min- 1
Two classes of FT muscle are identifiable in rat skel-
Phosphorylase 14 115 171 24, 608 etal muscle. In the sedentary animal one type (FG) is
Phosphofructokinase 21 69 100 24,29,608 white to the eye, whereas the other is deeply red
Pyruvate kinase 64 493 696 24,608
Lactate dehydrogenase 205 486 773 24,659
(FOG). Fibers from FG muscle have high activities of
Glycogen synthase 6 10 5 679 enzymes of the Embden-Meyerhof pathway but low
a-Glycerophosphate 5 26 57 24 activities of the enzymes for end-terminal oxidation.
dehydrogenase This high anaerobic capacity is characterized by activ-
Triosephosphate 175 432 607 24
dehydrogenase
ities of PHOS and PFK that are 5-10 times higher
Hexokinase 2 2 0.8 24, 659, 679 than those of the ST muscle. This metabolic profile
Succinate dehydrogenase 7 9 5 608 suggests a primary reliance on the anaerobic break-
Citrate synthase 23 41 9 29, 723 down of glycogen. The FOG portion of the FT muscle
Mean activities measured at 25C. SO, slow twitch, oxidative; possesses high activities for both glycolytic and oxi-
FOG, fast twitch, oxidative, glycolytic; FG, fast twitch, glycolytic. dative enzymes. This tissue can have higher activities
570 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

for end-terminal oxidation than SO fibers. This situa- TABLE 6. Water Spaces and Electrolytes in
tion is distinctly different from that of man where ST Predominantly Red (SO) and White
fibers have the higher oxidative potential. Note that (FG and FOG) Muscles
all of the different types of fibers found in rat skeletal
Pre-
muscle can be identified on the basis of differences in Pre- dominantly
the contractile proteins. dominantly White Species Ref.
An important result from single fiber analysis is the Red (SO) (FG and
FOG)
finding of a wide variation in the content of enzymes
Total H 2O, 344 310 Rat 158
for ATP production when comparing fibers of the ml/l00 g dry wt 325 308 Rat 657
same type from a single muscle (347, 468, 554, 651- 350 339 Rat 116
653). Both SDH and PFK activities varied up to 50% 324 329 Guinea 109
in ST fibers in the muscle from one subject (202, 203). pig
Part of this variation can probably be attributed to H 20 extracellular, 72 46 Rat 158'
ml/l00 g dry wt 53 33 Rat 657'
the 5%-10% variability in the precision of weighing the 39 35 Guinea 109t
fragments of fibers on the quartz balance. Furthermore pig
the amount of extramuscular material remaining on H 20 intracellular, 272 264 Rat 158
the fibers may vary from fiber to fiber. These two ml/l00 g dry wt 272 275 Rat 657
285 294 Guinea 109
factors could account for 5%-15% of the observed pig
variability in enzyme activities, but they cannot de- Na in muscle, 15 11 Rat 158
tract from the very large differences that exist in the mmol/l00 g dry wt 14 9 Rat 657
enzyme content of fibers of the same type. This obser- 14 8 Rat 116
vation has been substantiated by quantitative histo- [Na], mM 13 10 Rat 158
23 13 Rat 657
chemical studies where variations in staining intensity 28 19 Rat 109
were shown to exist for fibers in different motor units 44 50 Guinea 109
(555-557). This variability does not exist for fibers pig
belonging to the same motor unit (511-513). Quanti- K in muscle, 38 45 Rat 158
mM/l00 g dry wt 42 47 Rat 657
tative histochemical studies revealed that the varia- 44 51 Rat 116
tion in enzyme content along the length of a fiber is [K];, mM 141 179 Rat 158
small (558). This can account for the relative consist- 154 169 Rat 657
ency of enzyme activities when muscle biopsy samples 138 172 Guinea 109
are divided by cutting across the longitudinal axis of pig
Mg in muscle, 4.6 5.5 Rat 116
the fibers. The uniformity of structural characteristics mM/ 100 g dry wt
along the length of a skeletal muscle fiber supports
Values are means. ' Inulin space. t Chloride space.
these findings (212).
Ionic Composition of Skeletal Muscle chlorine, sulfur, or phosphorus (478, 727). Magnesium,
on the other hand, appeared to be slightly higher in
The various fiber types also contain different
amounts of intracellular ions (Tables 6 and 7). Sodium the FT than in ST fibers. These ions may not be
evenly distributed within the muscle fiber (478, 727).
is low in all fibers but the FT fibers contain only about
50% of that found in ST fibers. This is true for rat
In this context we add that the rather large variation
muscle but species differences may exist. Campion in intracellular space of a muscle that exists in the rat
(109) has reported slightly higher values in guinea pig may be related to the percent fiber composition. The
higher the percentage of ST fibers, the larger the
muscle with no difference between ST and FT fibers extracellular space of the muscle (443,657). In human
(Tables 6 and 7). In humans, the sodium content of
skeletal muscle such a relationship has not been ob-
the muscle fiber appears to be quite low with no served (641). There is also some variation between
difference between fiber types. Species differences human skeletal muscles (33-53 ml/g dry wt), but there
may also be present for intramuscular potassium con-
is no explanation for this rather large variation.
centrations. Rat and guinea pig muscle fiber types are
different: the concentration of K+ of ST fibers being Summary
140-150 mM whereas the FT fibers have a K+ concen-
tration of 170-180 mM. In man no differences can be Some of the major similarities and dissimilarities in
detected when comparing the different fiber types, the properties of the fiber types in the skeletal muscle
the mean value for both ST and FT fibers being from various mammalian species may be summarized.
approximately 160 mM. Recently electron probe anal- The first distinguishing feature is clearly the time to
ysis has been used to study electrolyte concentration peak isometric tension. On this basis FT and ST motor
and intracellular distribution. In addition to confirm- units can be identified. This feature is most easily
ing that K+ is of similar concentration in the ST and demonstrated for the limb muscles of animals. From
FT fibers in human skeletal muscle, with this method such studies clearly the time to peak isometric tension
no differences between fiber types have been found for and one-half relaxation time for the FT and ST units
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 571

TABLE 7. Muscle Electrolytes in Healthy Subjects imately 25% decline in the force developed during a
similar period and type of stimulation. The differences
Muscle Na m Km Mgm Ref.
are more pronounced when comparisons are made
mmol/100 g FFW between the FF units of cats and the FT b fibers of
Vastus lateralis 11.6 44.7 49 man. The force of FF units falls to near zero after 1
(2.7) (2.0) min of stimulation. In contrast the FT b fibers in human
Vastus lateralis 15.9 43.1 284
(2.9) (4.1) skeletal muscle retain up to 40% of the initial force
Different' 12.1 43.3 3.73 700 developed after 50 min of stimulation and 3,000 con-
(2.0) (2.5) (0.58) tractions. The FTa fibers of man are more fatigue
Vastus lateralis 9.3 46.7 4.48 50 resistant than the FR units of the cat. In man the ST
(1.5) (0.9) (0.08)
and FTa units have similar fatigue patterns, whereas
mmol/100 g dry wtt in the cat the FR units lose about 50% of their initial
Triceps brachii 12.7 45.0 3.86 641 force-developing capacity within 5 min of stimulation.
(5.0) (2.0) (0.33)
Vastus lateralis 8.9 44.9 4.12 641
The metabolic potential of the fiber types differs in
(2.5) (5.4) (0.18) various species. The most obvious difference is be-
Soleus 12.5 43.3 4.07 641 tween the FTa fibers in human skeletal muscle and
(3.3) (4.7) (0.45) FOG fibers found in many other species. The FTa fiber
Triceps brachii has a rather low triglyceride content and a low con-
ST fibers 13.0 44.0 3.98
FT fibers 11.6 46.2 4.15 641 centration of enzymes for ,B-oxidation. The enzymes
Homogenate 11.7 44.5 3.79 for the citric acid cycle and electron-transport chain
Vastus lateralis are usually present at lower concentrations than those
ST fibers 8.0 42.6 4.58 found in the ST fibers in the muscle of sedentary man.
FT fibers 8.9 43.0 4.76 641
Homogenate 8.3 44.2 4.12 This is in sharp contrast to the FOG fiber in the cat,
Soleus where the oxidative system is equal to or higher than
ST fibers 9.6 42.6 4.36 that found in the SO fibers. Briefly, we feel that
FT fibers 9.6 43.2 4.52 641 striking differences exist in the characteristics of fibers
Homogenate 10.7 41.8 4.09 found in human skeletal muscles as compared with
Values are means with 1 SD in parentheses. FFW, fat-free weight; those of other species. These differences are exempli-
ST, slow twitch; FT, fast twitch. ' In 6 subjects from sartorius
or pectineus muscles and in 6 subjects from the internal oblique
fied most dramatically by comparisons of the FTa and
muscle. t Fat content averaged 8% (5%-14%) of dry weight. If the FOG fibers. A major difference is in the signifi-
expressed per 100 g FFW, value should be increased by this amount. cantly greater resistance of the FTa and FT b motor
units of man to fatigue as compared to all FT motor
vary not only among species but also between muscles units of the cat.
of the same animal. For human skeletal muscle few
precise data are available, but indications are that the
MUSCLE FIBER COMPOSITION IN HUMAN
time to peak isometric tension is about 40 ms for FT
SKELETAL MUSCLE
units and 80-100 ms for ST units. It is unknown
whether differences exist between the subgroups of
FT units or what variation exists for the ST and FT There is considerable interest in the percent com-
units of different muscles. position and the size of the different fiber types in the
The ability of FT and ST units to develop force per skeletal muscle of normal humans and of athletes.
unit transectional area of muscle is a matter of contro- Table 8 is a compilation of such data for normal
versy. There are reports of major differences in the sedentary subjects as reported by a number of labo-
tension produced per square centimeter by the ST and ratories. Table 9 is a summary of the fiber composition
FT units of the cat. In the rat, evidence seems to and fiber area for several muscles from subjects who
suggest that the force-developing capacity is similar were either elite athletes or who had undergone spe-
for both FT and ST motor units. The force developed cific training programs. In addition to the data com-
per square centimeter for mixed-fiber skeletal muscle piled in Tables 8 and 9, other studies containing more
of man appears to be greater than the values reported information on this subject can be found in references
for either cat or rat skeletal muscle. Although direct 47, 118, 136, 288, 289, 300, 315, 405, 430, 574, 579, 598,
measurements of the force per unit area of ST or FT 673. These data are mostly from studies where the
motor units are not available for human muscle, they muscle samples were obtained by the biopsy (either
appear to be similar. the needle or open) method. Data are also available
Some similarities exist in the fatigue characteristics from entire muscles obtained at autopsy. Values for
of the motor units in cat and human skeletal muscle. fiber composition and fiber size from such studies can
On the other hand there are also major differences. In be found in references 173,401-403,406,407,520,562.
the cat the tension developed by ST units remains Comparisons have also been made between the open
rather constant over a 60-min period of stimulation, and needle biopsy methods (160).
whereas in human skeletal muscle there is an approx- Perhaps the most extensively studied human muscle
572 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

TABLE 8. Summary of Some Published Values for Percent Distribution and Size of Fibers
in Limb Muscles of Humans as Estimated From Biopsy Samples
Slow-Twitch Fibers Fast-Twitch Fibers
Sex Muscle No. Mean Range Ref.
X Area, X Area,
% Range Range % Range
pm' X 10' I'm' X 10'

VM 11 42 26-63 58 174
BB 7 49 39-61 51 174
M,F VL 6 57 50-71 45.6 29.7-60.3 43 48.9 33.1-63.9 177
M,F BB 7 48 37-61 40.6 27.2-54.3 52 61.4 34.2-87.1 177
M G 2 64 55-69 33.7 33.0-34.4 36 46.0 39.8-50.2 177
M S 2 72 65-78 53.3 47.8-58.7 28 94.3 71.1-117.5 177
M VL 26 34 24-52 36 13-73 40.2 11.4-98.4 64 52.2 17.4-94.7 261
M D 26 34 24-52 46 14-60 54 261
M VL 8 23-32 48 29-65 45.6 33.0-60.3 52 50.7 37.0-71.7 175
M VL 6 28-37 32 18-41 55.0 30.6-92.0 38 66.4 43.1-75.9 260
M VL 4 16-18 41 50.6 59 55.0 687,688
M G 19 27 58 54.6 42 49.5 132
M G 11 27 17-42 53 38-73 57.0 34.0-87.2 47 49.7 38.8-68.6 130
F G 10 22 20-30 51 27-72 38.8 25.5-50.4 49 41.9 25.7-61.6 130
M VL 4 36 20-48 33.0 22.6-41.8 64 37.6 22.3-51.9 565
F VL 5 36 27-42 27.8 20.5-35.8 64 29.1 17.1-41.6 566
M VL 19 27 58 54.6 42 49.5 96
M VL 69 16-18 54 48.4 32" 52.7 398
13"
lc
M,F VL 5 24-41 51 47-67 49 272
M,F S 11 24-41 80 64-100 20 272
M,F G 6 24-41 60 45-82 40 272
M G 4 24 20-26 51 37-66 43.1 31.6-51.0 49 47.3 35.0-69.3 8
M S 4 24 20-26 71 53-88 75.2 49.5-90.0 29 110.6 81.1-147.3 8
M VL 8 24 20-31 53 45-62 47 681
M VL 9 23 49 26-60 52.9 37" 55.7 289
18h 51.5
M VL 5 24 47 55.9 29" 68.0 129
24" 62.7
M G 19 32 53 23" 131
24"
F VL 24 24 51 49 108
M VL 6 6 43 42-72 57 45
F VL 6 7 56 41-68 44 45
M VL 11 26 20-29 60 29.4 40 36.6 445
M VL 10 35 30-39 63 28.5 337 35.1 445
M VL 8 43 40-49 52 31.3 48 33.6 445
M VL 12 55 50-59 28.8 52 28.0 445
M VL 10 62 60-69 45 22.6 55 21.2 445
M,F 59 21-83 173

Autopsy Material
S 20 70 12-95 30
Med. gast. 24 50 14-84 50
Lat. bast. 9 48 37-62 52
Whole gast. 33 50 33-63 50
Vast. into 14 47 30-71 53
VL deep 10 35 22-50 65
VL superf. 15 30 11-53 70
VL whole 25 32 19-48 68
BB autopsy 17-30 42 34-51 58 408
D 53 43-63 47 408
VL 38 27-48 62 408
M, male; F, female; G, gastrocnemius; S, soleus; BB, biceps brachialis; D, deltoid; VL, vastus lateralis; VM, vastus medialis; X, cross-
sectional area. a Fast twitch, a type. b Fast twitch, b type. c Fast twitch, c type.

is the lateral portion of the quadriceps femoris (vastus In an attempt to provide further information concern-
lateralis). In an early study biopsy samples were ob- ing the normal fiber composition of this muscle, 69
tained from 74 male subjects from 17 to 58 yr of age, males and 48 females (Fig. 10), all 16 yr old and
including sedentary men and highly trained athletes representing a random sample for this age group, were
(261). For this group the average fiber composition studied (602). The mean fiber composition of the
was 52.2% ST with a range from 13%to 98% ST fibers. vastus lateralis muscle for this group was 54% and 52%
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 573

ST fibers for the males and females, respectively. ST fibers, some muscles, like the soleus and triceps
Within the FT fibers the FT. fibers were approxi- brachii, have a predominance of either ST or FT
mately twice as common as the FT b fibers. Similar fibers. In man the respiratory and trunk muscles have
mean values for the percentages of ST, FT., and FT b mixed ST and FT fibers. The diaphragm and intercos-
fibers were observed in studies of 26 men and 25 tal muscles of man contain approximately equal per-
women around 25 yr of age (521). Thus ample evidence centages of ST and FT fibers (311). Muscles around
is available to suggest that in the vastus lateralis the spine appear to contain nearly 50% ST fibers but
muscle the ST and FT fibers are about equally com- a fairly wide interindividual variation as is seen in the
mon, and no differences exist between the sexes. muscles of the extremities. In addition to the results
In the studies cited above, the relative percentage from autopsy studies, data are available from studies
of fibers was estimated from small muscle samples where several muscles in the same subjects were biop-
obtained with the needle biopsy (49) technique where sied and the fiber composition estimated (Fig. 12A).
fragments of 200-1,000 fibers are contained in each In all important aspects these findings are analogous
sample. The large variation observed in these samples to the autopsy study.
could be a reflection of a heterogeneous mixture of An important question is whether small muscle
fibers in the cross section ofthe vastus lateralis muscle. samples from a human muscle, such as those obtained
The variability of the relative frequency and of the with a biopsy technique (49), will give acceptable
size of the various fiber types has been examined in information about the fiber composition, fiber size, or
whole cross sections of muscles obtained at autopsy chemical composition of the entire muscle (160, 180,
(173, 186, 402, 403). 181,520,563). Repeated sampling from the same mus-
A variation in the relative occurrence of the fiber cles gives a coefficient of variation of 5%-10% for fiber
types in a muscle does not exist but it does exceed 5%- composition and size (SD in percent of the mean fiber
15% when calculated for adjacent regions of the mus- size or fiber composition). Large samples do not reduce
cle. A tendency for ST fibers to comprise a higher this variation substantially nor does an open versus
percent of the total in the deeper parts of the muscle needle biopsy produce a significant difference (186,
is sometimes found, but this is limited and does not 261). The problem of a differential distribution of
exceed 5%-10%. Fiber size varies slightly in different fibers in the central as compared to the superficial
parts of the muscle with the ratio between ST and FT part of a muscle can be accommodated by a greater
fibers being relatively constant throughout the entire precision in the sampling site (186). We may justifiably
muscle. Another approach to the study of the variation conclude that for most cases the mean value for a
in fiber composition and size is to take multiple biopsy group of subjects closely reflects the true value for a
samples from the same muscle. When this was done in given muscle. However, there are instances where
the vastus lateralis muscle the coefficient of variation considerable deviation from the mean value may occur
for the relative occurrence of a fiber type was 5%-15% (186, 644); for these more reliable informaton can be
and for the size of the corresponding type it was 5% obtained from multiple biopsies taken from different
(261, 302, 686). A similar pattern of variation was also sites. This is especially true for the assessment of the
found when data from 36 human muscles were ana- percent fiber composition.
lyzed (406, 407). Other studies of the vastus lateralis Similar problems may also be encountered in the
muscle and the biceps brachii confirm these findings determination of substrate concentrations and enzyme
(520). activities where these are distinctly different for the
The large range of the percentages of ST and FT different fiber types. This problem can only be ade-
fibers observed in the population in these studies quately resolved by analysis of individual fibers. This
implies that for a certain percent of the population of problem also extends to the analysis of substrate
males and females, their muscles are predominantly of changes in muscle where only select motor units have
one or the other fiber type. This interindividual vari- been active. Under these conditions analysis of whole
ation appears to be genetically determined because muscle samples will seriously underestimate a change
studies with mono- and dizygotic twins have shown such as the depletion of glycogen or an increase in a
almost identical fiber composition of the vastus later- metabolite.
alis muscle in the monozygotic but not in the dizygotic Human beings, in contrast to other species, have a
twins [Fig. 11; (431)]. more homogeneous mixture of fibers in nearly all
The various muscles of the human body differ in muscles. Thus the higher degree of specialization, with
fiber composition. The extent of this variation is illus- the result that a single fiber type is seen in a muscle or
trated by data from an autopsy study where the same large area in some animals, rarely occurs in man.
muscles from several subjects were analyzed (173,402,
403,406,407,667). The results from six men and three
women, who died suddenly without having a known MOTOR- UNIT RECRUITMENT
muscle disease, are given in Figure 12B. It is apparent
that some similarities exist among muscles from the The contractile and metabolic properties that com-
same person. It is also apparent that although most bine to produce the physiological characteristics of the
muscles have a mean fiber composition of about 50% individual motor units in skeletal muscle enable them
574 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

TABLE 9. Summary of Some Published Values for Percent Distribution and Size of Fibers
in Limb Muscles of Humans in Training as Estimated From Biopsy Samples
Age Slow-Twitch Fibers Fast-Twitch Fibers
Sex Muscle No. Experiment Ref.
X Area, X Area,
Mean Range % Range Range % Range
urn" X 10' p.m' X 10'

M VL 6 33 29-40 32" 18-41 55.0 30.6-92.0 68 66.4 36.8-95.8 Endurance training on 688
36 b 27-42 67.8 55.5-89.0 64 61.4 43.1-76.0 cycle ergometer, 6 mo
M VL 4 24 18-33 61 48-73 86.5' 58.0-127.6 39 99.5 75.4-147.9 Elite bicyclists 261
D 51 40-64 54.7' 40.6-72.5 49 73.4 46.4-92.8
M VL 4 26 25-27 61 45-72 64.4' 36.6-91.4 39 51.0 36.6-65.8 Elite canoeists 261
D 58 48-66 82.4' 58.5-131.6 42 83.9 54.8-109.8
M VL 4 25 23-29 46 25-60 60.4' 17.4-101.5 54 95.6 58.0-145.0 Weight lifters 261
D 53 43-67 55.5' 29.0-75.4 47 89.2 43.5-145.0
M VL 8 23 19-33 59 53-70 41 Distance runners 261
M VL 11 52 47-58 69 47-96 31 Orienteers 261
D 63 31-98 37
F G 2 20 18-21 27 27-28 37.5 35.4-39.4 73 39.3 33.7-45.0 Trained sprinters 130
M G 2 20 17-22 24 21-27 58.8 39.8-77.8 76 60.3 58.8-61.9 Trained sprinters 130
F G 7 20 16-25 61 44-73 60.7 30.8-99.5 39 56.4 40.1-75.0 Trained middle-distance 130
runners
M G 7 23 19-32 52 41-69 61.0 45.5-84.5 48 71.2 48.9-92.1 Trained middle-distance 130
runners
M G 5 24 20-32 69 63-74 66.1 36.4-101.1 31 76.3 47.3-113.3 Trained distance runners 130
F G 3 22 21-23 49 37-61 41.6 35.0-50.8 51 51.1 43.5-66.2 Long and high jumpers 130
M G 2 29 26-32 47 44-49 47.2 44.8-49.6 53 65.2 63.0-67.5 Long and high jumpers 130
F G 3 21 17-26 42 41-42 48.6 42.6-54.6 58 45.7 42.7-48.7 Javelin throwers 130
M G 3 25 23-30 50 46-56 55.9 25.7-82.5 50 57.7 42.1-76.1 Javelin throwers 130
F G 2 24 21-26 51 48-54 51.9 32.9-70.9 49 58.5 47.7-69.4 Shot and discus throwers 130
M G 4 27 21-32 38 13-52 77.0 50.4-103.5 62 94.8 91.3-97.2 Shot and discus throwers 130
d
M VL 4 21 17-28 69 60-83 20 14-30 Distance runners after 18 399
lO e 1-20 wk aerobic training
I' 0-1
M VL 4 21 17-28 52 34-77 18d 7-28 Distance runners after 11 399
18e 4-29 wk anaerobic training
12' 7-15
M G 13 35 55 43 d Trained distance runners 131
2e
12 23 23 47 d
2e
F G 18-26 39 32.5 61 35.0 Sprinters 290
F G 18-26 54 37.5 46 30.0 Pentathletes 290
F G 18-26 63 32.5 37 27.5 Middle-distance runners 290
F G 18-26 73 36.0 27 21.0 Distance runners 290
M G 26 56 54.3 44 54.2 Well-trained distance 227
runners
M VL 8 68 Elite orienteers 398

M G 7 67 Elite orienteers 398


CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 575

TABLE 9-Continued
Age Slow- Twitch Fibers Fast-Twitch Fibers
Sex Muscle No. Experiment Ref.
X Area, X Area,
Mean Range % Range pm' X 10' Range % Range
/lm' X 10'

M D 4 68 14 d Elite orienteers 398


17e
0'
M VL 3 21 20-22 60 51-70 40 Elite skiers 681
M VL 11 25 57 63.3 43 61.2 Elite cyclists 96
MVL 1125 53 60.6 47 57.6 Well-trained cyclists 96
F VL 720 51 54.9 49 52.2 Well-trained cyclists 96

F VL 5 23 20-32 48 24-82 43.1 31.1-71.7 52 38.2 15.2-76.9 Field hockey players 566
M VL 3 45 30-60 44.3 31.6-58.9 55 67.7 58.1-76.6 Weight lifters 565
M VL 3 44 29-54 46.1 33.9-69.0 56 43.1 25.1-69.0 Distance runners 565
d
M VL 5 24 45 61.1 30 73.7 Leg 1 control 129
25 e 67.7
M VL 5 24 42 58.9 35 d 73.8 Leg 1 after 7 wk of 129
23 e 71.2 training 6 s,
4 times per wk
M VL 5 24 48 48.7 62.3 Leg 2 control 129
57.7
M VL 5 24 47 49.6 75.9 Leg 2 after 7 wk of 129
56.3 training 30 s,
4 times per wk
M D 6 23 18-28 53 41-74 47 Elite canoeists 682

M G 14 26 21-32 79 50-98 83.42 48.5-151.4 21 64.9 31.8-115.2 Elite distance runners 132
d
M VL 19 22 50 20-71 50.9 38 58.7 Elite ice hockey players 289
12 e 53.6
M VL 8 20 16-29 44 24-55 45.5 35.7-65.8 56 74.3 59.5-92.4 Weight lifters 175

M VL 4 16-18 41" 50.6 59 55.0 Sprint training 687


44 b 51.9 56 57.4
M, male; F, female; VL, vastus lateralis; D, deltoid; G, gastrocnemius. a Before training. b After training. C Samples for single
representative subjects. d Fast twitch, a type. e Fast twitch, b type. r Fast twitch, c type.

to engage in a wide variety of activities. The ST motor to develop force per unit of cross-sectional area does
units, in all species, are well designed for prolonged not appear to be significantly different from that of
activity, where ATP can be produced by directing FT fibers. This would reduce the need for an early
substrate flux through the oxidative pathways of the recruitment of the FT motor units when additional
mitochondria. In animals other than man the FT tension development is required. Second, the oxidative
motor units in red muscle rely primarily on either the potential of the FTa fibers is considerably lower than
terminal-oxidative process or the glycolytic pathway that of the ST fibers in the muscle of sedentary man.
(or both) for ATP production. These motor units For most other animals the mitochondrial density of
appear uniquely suited for joining the ST units during the FTa fibers may be equal to or in some cases higher
prolonged activity when the intensity is relatively than that of ST fibers.
high. The FT motor units in white skeletal muscle The systematic use of the different motor units in
(FT b ) appear best suited for high-intensity short-du- response to distinct physiological demands depends on
ration activity, where a glycolytic degradation of gly- the existence of an orderly procedure for their recruit-
cogen to lactate is the primary method for ATP pro- ment by the central nervous system. This system is
duction. based on the existence of motoneurons of varying size,
Some differences exist in the properties of FT motor threshold for activation, and conduction velocity.
units contained in human skeletal muscle as compared These properties of nerves were identified by Hursh
with those of other animals, which may result in (377) and Rushton (597). Their importance in the
slightly different patterns of use for these motor units control of motor recruitment was elaborated by
during locomotion. First, the capacity of the ST fibers Henneman and co-workers (327-331). In this scheme,
576 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

from the fibers in biopsy samples) and electrophysio-


logical data (143-147, 293, 294, 299, 308, 493, 494). The
method of biopsy and glycogen depletion is limited to
exercise of sufficient duration and intensity to produce
25 a discernible loss of PAS stain in the fibers. In some
instances the metabolic profile of the fibers results in
c
20 underestimating the involvement of ST units. Thus
o \ during high-intensity exercise the loss of glycogen from
:J
~15 \~ FT b units would be greater than from ST units simply
~ n, 45 \ d'n' 70
because the ST units would also consume large
Cl 10 1Syears \lSyears amounts of oxygen, free fatty acids (FFA), and glucose,
A \ resulting in a smaller degradation of glycogen. Electro-
I. \ physiological methods lack a definitive proof of the
5 / \ type of motor unit from which the electrical potential
/ \
/ -, is recorded.
./ <,
~ Histochemical studies (Fig. 13) have verified a pri-
10 20 30 40 50 SO 70 80 90 100 'f, mary involvement of ST motor units during low-inten-
ST, vastus lateralis
sity exercise in man (262, 270). When such activity
FIG. 10. The distribution of relative occurrence of ST fibers in is prolonged or when its intensity is above a certain
vastus lateralis in young men and women. [Adapted from a study level, there is a progressive involvement of FT motor
by Hedberg and Jansson (319); some results are presented in Saltin
et al. (602).] units, with the FTa units being involved first, until, if
the exercise extends to exhaustion, all motor units will
have been involved (263). With high-intensity dynamic
TWIN A exercise, that is, above maximal oxygen uptake
80 (\7'02 max) capacity, all types of motor units may be
o o activated (263, 270). For some individuals exhaustion
does not result in a complete depletion of glycogen
from all FT fibers regardless of whether the exercise
60 has been of a moderate or high intensity (262, 270).
The exercise intensity required to activate FT motor
units is debated. It has been suggested that this may
/,0 o occur at intensities as low as 60%-70% of the \7'02 max
and that this may be responsible for the elevation of
lactate in the blood at these exercise intensities (392,
598). Definite proof for this concept is lacking in the
20 published literature, and data are available to suggest
that it is unlikely. The increase in the lactate concen-
tration of blood that occurs during prolonged, moder-
TWIN B ately severe (60%-70% \7'02 max) exercise usually peaks
20 40 60 80 at about 10-20 min and then declines toward rest
11. Intrapair comparison of slow-twitch fiber distribution of
FIG.
values as the exercise continues (270, 341, 418). If the
m. vastus lateralis in monozygous (e) and dizygous (0) twins. [From lactate production is a result of FT fiber use, its decline
Komi et al. (431).] could be explained either as a fatigue and inactivation
of these fibers or by assuming that they have switched
now commonly referred to as the size principle, ST to terminal oxidation to support their energy require-
motor units are innervated by small, low-threshold, ments. If the FT fibers were exhausted they could be
slowly conducting motor nerves; FT motor units are expected to be depleted of glycogen as occurs during
innervated by large, higher threshold, fast-conducting short, heavy exercise (263). This is not the case. Since
motor nerves. Rather than discrete differences in mo- the power output is constant during such exercise a
toneurons it appears that a continuum of thresholds loss of some motor units would necessitate the addi-
for activation exists. In this manner a systematic pro- tion of others. Based on the concept of ST recruitment
cedure for mobilizing motor units exists whereby the before FT units, this would imply addition of more FT
tension requirements for a specific muscular contrac- units (143-145), but this would produce more lactate
tion pattern can be initiated by the central nervous rather than less. If the FT fibers had converted to
system. oxidative metabolism, the total oxygen uptake would
Evidence for an orderly recruitment of motor units increase. This does not occur (262, 270). As the exercise
in man during a variety of physical activities has come continues, however, and ST fibers become glycogen
from both histochemical (133, 237, 262, 263, 267, 270, depleted, there is evidence of a use of FT units (262,
271, 286, 287, 522) (based on the depletion of glycogen 270). This occurs without any rise in the lactate con-
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 577

.,.
100 A 100

90 90

80 80

70 70

60 60

SO 50

40 40

III
30
-
~

.c 30

"i-
~
u 20 20

1 I . f
~ Gastroc- Vastus Soleus Triceps
0 % n e rni us lateralis brachii

-
'iii 100
0 B
100

..
Cl 90 90

u
C
80 80
~

~
70 70

60 60

30 50

40 40

30 30

20 20

1 f
Gastroc- Vastus Soleus Triceps Bi c e ps Deltoi-
n erni u 5 late-ral i 5 brachii brachi i deu5

FIG. 12. Relative occurrence of ST fibers in some muscles of the body. A: muscle samples are
obtained by multiple needle biopsy samples or (B) postmortem within 24 h after death. [A from
Sjegaard (641) and G. Sjegaard, unpublished materiaL B from Johnson et aL (406).]

centrations of the blood or in total-body oxygen uptake eters that are mechanically braked and have light
(270). The latter circumstances suggest either that the flywheels often possess little inertial momentum. Thus
FT fibers possess adequate mitochondrial enzymes for each pedal thrust a brisk contraction may be
and receive sufficient blood flow to support the ter- needed to keep a steady pace. From EMG studies it is
minal oxidation required for the levels of tension they known that the threshold for activation of a motor
produce during such exercise or that the lactate pro- unit is reduced during brisk or ballistic-type contrac-
duced is taken up and oxidized by other muscles. Such tions (143, 146). This situation basically applies to
lactate could also be cleared by the liver. dynamic exercise performed by man. Motor unit in-
Some of the discrepancies that exist in the literature volvement in various gaits has been studied, e.g., in
concerning the fiber type involvement at different the rat, lion, and horse (17, 19, 21, 457, 663). It is
exercise intensities may be attributable to the use of apparent from these studies that during walking and
different modes of exercise. For example, cycle ergom- trotting at rather low intensities both ST motor units
578 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

% FTb
100

50

a
0'. FT a
FIG. 13. Schematic illustration of intensity of 100
periodic acid-Schiff (PAS) stain (glycogen) in hu-
man skeletal muscle fibers at rest and after various
times during prolonged exercise at relative work
intensities ranging from 31% to 85% of the subject's
maximal oxygen uptake. Graph is a summary of
50
several studies. Findings at 74% V02 max show the
PAS stain evaluated by microphotometry, whereas
in the other studies results are based on a subjec-
tive rating (dark = filled; and white = unfilled,
a
with various levels between as crosshatched and % ST
hatched). [Data from Gollnick, Saltin, et al. (262,
263, 270, 271). Findings at 74% V02 max from K. 100
Vellestad, unpublished material.]

50

Ti me, min
a o 40120180 20 120 20 120 12 36
Rest Exercise-
0.28 1.39 2.54 3.49 3.51

Energy demand 9 31 60 74 85
0'0 of '\102 max
and FT motor units of oxidative type (FOG) become consideration the knee angle at which the peak force
depleted of glycogen early in the exercise. In contrast, was developed but not the speed of contraction. When
the FG motor units do not become depleted of glyco- the speed of contraction was also considered, the rel-
gen in these gaits even at high speeds but only during ative values ranged from 20% to 40% of the MVC that
galloping. This is additional evidence for a basic dif- could be produced at the speed of contraction obtained
ference between the FT motor units of man and other at 60 rpm. Thus even at exercise intensities that pro-
animals that have been studied. duce exhaustion in 4 min, less than one-half of the
These findings do not detract from the concept of strength of the muscle was utilized.
an orderly recruitment of motor units but point to In experiments where static contractions were held
species differences in the programming of the recruit- with the knee extensors at tensions representing from
ment of the fiber types. This has implications for how 10%-20% of the MVC, only ST units became glycogen
they are used in various activities. depleted (270). At higher tensions FT units also be-
Clearly recruitment order in man may be related came depleted of glycogen. This suggests that with
either to the requirement for tension development or this type of muscular activity the availability of oxygen
to the availability of oxygen or to both. To obtain and the development of force influenced recruitment
some perspective of what fraction of the voluntary of FT units since blood flow in the knee extensor group
contractile strength is used in dynamic exercise, peak is restricted during sustained contraction above about
force for a pedal thrust during cycle ergometer exercise 20% MVC (58,59,376).
was measured (267, 269, 349, 640). Less than 1(\% of The EMG recordings from single fibers support the
the MVC was used at power productions demanding concept of an orderly recruitment of motor units in a
less than the subjects' V02 max. At exercise intensities progression from ST to FT units (143-147, 279, 493,
eliciting V02 max, the corresponding value ranged from 494, 539). The observation that the individual motor
10% to 15% of MVC. These measurements take into unit is activated at specific levels of tension and ceases
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 579

discharging when the tension falls below this set level muscle by electrical stimulation or by voluntary means
points to the level of tension development as the can produce very different mechanical and metabolic
primary factor in controlling motor unit recruitment demands on the muscle, depending on which fibers are
(53-55). Though there is evidence for an activation of engaged in generating the force, this must be consid-
FT motor units before or without ST units during ered when discussing muscle adaptation. To evaluate
high-intensity exercise (293, 294, 661), the data in whether the mode of usage may elicit different adap-
support of this concept are equivocal. tive responses, exercise is categorized as: 1) high-re-
There are reports using either histochemical or elec- sistance, few-repetition exercise (strength training); 2)
trophysiological techniques indicating exceptions to low-resistance, high-repetition exercise (endurance
the orderly treatment of motor units as described training); or 3) varying intermediate combinations (for
above (294, 295, 661). The histochemical studies are example, sprint training).
difficult to evaluate since there is a lack of definite Clearly the changes in skeletal muscle that accom-
proof as to the ST fiber involvement. In such studies pany either use or disuse as described in this chapter
the reduction in glycogen was too small to be evident involve alterations in either the rate of protein synthe-
from histochemical staining procedures. The EMG sis or degradation. Recently attempts have been made
recordings from single ST and FT fibers in brisk to investigate these changes and to determine the
contractions or at contractions close to MVC demon- mechanisms by which they are induced and controlled
strate that FT units may be electrically active before (60, 62, 244-246, 313, 332, 339, 350, 393, 414, 610, 618,
ST units, but the ST fibers are not silent (143). In 620, 677). This is an area for future investigation.
voluntary efforts with simultaneous, preprogrammed
activation of neurons in the motor cortex (40, 147), it
could be anticipated that FT units of muscle would Muscle Size
display electrical activity prior to ST units simply In terms of its ability to adjust its size to physiolog-
because of a difference in the conduction velocity of ical demands, skeletal muscle is a very plastic tissue.
the motoneurons and the number of interconnecting This is illustrated by the changes in weight that occur
neurons. The recruitment pattern might also differ in during normal growth and development and in the
reflex activation of motor units by input from sensory adult or growing animal in response to alterations in
receptors in the skin. activity patterns. Since skeletal muscle consists of
The specific mechanism or sensing system to which about 85% (by weight) fibers and 15% extrafiber ma-
the central nervous system responds with varying terial (224, 348,429,447,458), a change in total weight
patterns of motor unit recruitment is unknown. It is is a simple, yet reliable, method for estimating changes
easy to envisage a system centered around the stretch in the fiber component of muscle. Exceptions to this
receptors in muscle spindles or golgi organs. Informa- are instances where experimental perturbations or
tion from these receptors could signal the need for pathological changes produce modifications in the wa-
adding or subtracting motor units from the contrac- ter and collagen content of muscle (16, 378). The
tion. During prolonged submaximal exercise, where it growth potential of skeletal muscle can be illustrated
appears that a progressive recruitment of motor units in inbred animal strains such as the rat or chicken. For
occurs starting with ST and finally using all units the rat, the limb muscles increase about 28-fold from
including FT units, this could occur as a result of fetal stage to 80 days (190) and 9- to 21-fold in weight
failure of the ST units to produce the needed tension from the 16th to the 86th day after birth (191). For
as their glycogen stores are depleted and their ability the chicken, the weights of the gastrocnemius and
to produce the ATP needed to support contraction is pectoralis muscle increase 40- to 90- and 300- to 600-
diminished. fold, respectively, from hatching to 266 days of age
(502). From hatching to 10 wk of age the sartorius
muscle of the chicken increased from 0.129 to 4.930 g
ADAPTIVE RESPONSE IN SKELETAL MUSCLE (745). Human skeletal muscles possess a growth char-
acteristic similar to that of other animals. This is
Different types of motor units exist in skeletal mus- illustrated by the increase in weight of the biceps
cles, and they are endowed with properties that brachii from about 2.0 g at birth to 110-150 g in the
uniquely qualify them for specific types of activity. In adult (B. Saltin, E. Nygaard, and A.-S. Colling-Saltin,
addition to the differences between major types of unpublished observations). In addition to illustrating
motor units there are also differences between motor the great growth potential for skeletal muscle, these
units that are histologically similar. Thus there is a data also demonstrate that the absolute increase in
broad array of contractile speeds, fiber numbers, and the size of muscle depends on its function as deter-
metabolic potentials for the motor units in a single mined by its location on the skeleton.
muscle. This section considers what effects growth With changes in muscle size HS a result of growth
and patterns of use (either overload or inactivity) have and maturity there are also changes in the chemical
in establishing, maintaining, or changing the charac- composition of muscle of the fetus as compared to that
teristics of skeletal muscle. Since activation of skeletal of the adult. Fetal skeletal muscle is about 90% water
580 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

(123-125, 153). At 4-7 mo of age this value is about studies is that there is a large increase in fiber size
78.5% water with only minor changes occurring there- during normal growth and development. An example
after until attaining the adult value of about 76% of such data is the report that the fiber diameter of
water. There are also major changes in the protein the pig increased from an average of about 7 /lm at
fractions of muscle (Fig. 14). This is exemplified by a birth to over 70 /lm in the adult (660). This lO-fold
2.8-fold increase in total protein from the 14th wk of change in diameter would be equal to about a 100-fold
gestation to the adult human being. Of the various increase in cross-sectional area if one were to assume
protein fractions, the biggest increase occurs in the that the fiber areas were geometrically similar (which
fibrillar fraction, which increases 3.5-fold. There are they are not). Other factors that influenced the mag-
also changes in the intracellular ion concentration nitude of the fiber enlargement were the strain of the
from fetal life to maturity (Fig. 15). animals and their state of nutrition. The lack of any
change in fiber number extended to instances where
POSTNATAL DEVELOPMENT. Nonhuman species. the total muscle weight had increased more than 600
There has been considerable interest in the question times during the growth period (507).
of the relative importance of changes in the size (cross- The number of fibers in the limb muscles of the rat
sectional area or diameter) and number of fibers in has been reported to be essentially unchanged over
animal muscle. This has been an active area of re- the period from 4-6 days postpartum to 300 days (190,
search for those interested in meat production. As a 191). The average fiber weight in the neonatal rat has
result, data are available on the size and in some cases been estimated to be slightly over 2 /lg as compared to
the number of fibers in the muscle of the chicken, pig, 22.4 /lg/fiber in the biceps brachii and 63.1 /lg/fiber in
sheep, rabbit, and steer (114, 219, 343, 410, 487, 490, the gastrocnemius muscle in the adult animal (191).
564, 585, 645, 660). The general conclusion from these The relative increase in weight per fiber exceeds that
0/0

100 Water

90
80

70

Sarcoplasmic Protein
60

40

20
FIG. 14. Changes in the percent water and concentra-
tion of protein in the sarcoplasmic and fibrillar fractions o
of human skeletal muscle as a result of growth and devel- mojo Fibrillar Protein
opment. [Adapted from Dickerson and Widdowson (153).] 140

13-14wks 20-22wks Newborn 4-7mlh


FE TA L INFANT ADULT
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 581

of the samples were from males. The samples were


fresh frozen and stained with histochemical methods
200 to identify the different fiber types. These data illus-

.'
trated that early in fetal life the muscle fibers had not
developed to a stage where they could be typed. For
150 '----- animals also, it is difficult to identify fiber types in
fetal life (157, 159, 240, 404, 475, 595). Some differen-
tiation of fibers into types appeared at about the 21st
100 wk of gestation and thereafter continued with differ-
~
<,
- K
entiation being nearly complete at approximately 1 yr
o - Na
0-
W .. - Mg
of age (Fig. 17). These studies revealed that at about
12 wk of gestation the average cross-sectional area was
-------.
E 50 A - P
36.3 }lm 2 This remained relatively constant until about
... 21 wk of gestation when ST fibers with an average
'------<0 0'
OL.-.......- .......- " " " - - - - - ' ........... area of about 128 }lm2 appeared in cross sections.
Feta I mths Newbarn mths I yr Adult
These ST fibers constituted about 3% of the total fiber
FIG.15. Intracellular ion concentrations for human skeletal mus- population with the remainder still being small, undif-
cle from fetal life to adulthood. The data points marked (') are ferentiated fibers. During the subsequent period of
averages of samples collected from the triceps brachii, vastus later- gestation the percent of fibers that could be identified
alis, and soleus of 6 male and 6 female adults. [Data from Dickerson
and Widdowson (153), except those marked (') from Sjegaard (641).] as a specific type increased as did the average cross-
sectional area of the fibers. At the time interval of 38
to 42 wk of fetal life, approximately 80% of the fibers
of the overall gain in weight during postnatal skeletal could be typed. These fibers averaged about 200 }lm 2
muscle growth. in cross-sectional area. At the age of 1 yr the cross-
In contrast to the above, there are reports of in- sectional area ofthe fibers ranged from 500 to 600 }lm 2
creases in the number of fibers in skeletal muscle of The cross-sectional areas reported by Colling-Saltin
the rat during the period from birth to 3 wk of age (72, are larger than those observed by Aherne et al. (2).
114,571) and in the muscles of an Australian marsupial This difference can probably be attributed to the
(71). Conversely, decreases in the fiber number of the different methods used to prepare the tissue.
dog, guinea pig, and rat have been reported with age Aherne et al. (2) used paraffin embedding as con-
(213, 214, 380, 571). trasted to the fresh-frozen tissue technique used by
Man. Aherne et al. (2) examined changes in the Colling-Saltin (123-125). Paraffin embedding produces
fibers of the deltoid, biceps brachii, rectus femoris, and a significant shrinkage of the tissue during the dehy-
gastrocnemius muscle of man in the age range of from dration procedure. Normally this amounts to about a
37 wk of gestation to 18 yr of age. This material was 20% reduction in area. However, since the water con-
from 22 individuals, 14 males. Only rarely was there tent of fetal muscle is considerably greater (e.g., see
more than one sample for a given age and not all years Muscle Size, p. 579) than that of postnatal muscle,
were represented. In this sample the fibers in the this could also contribute to the variability between
muscles at 37 wk of gestation ranged from 36.5 to 48.2 the fetal and mature muscles. Cross-sectional areas
2
}lm with the smallest fibers in the rectus femoris and ranging from about 2,500 to 10,000 }lm2 have been
the largest in the gastrocnemius muscles. Over the observed in cryostat sections of fresh-frozen adult
entire age range examined, there was a nearly linear human limb skeletal muscle (see Table 9). There are
increase in the cross-sectional area of the muscle fibers a number of other studies where fiber size was deter-
as a function of body dimension (Fig. 16A, B). Unfor- mined in muscle of children and adults (67, 74, 75).
tunately, the fibers were not subdivided into the dif- In addition to problems associated with methods of
ferent types. In mature individuals, the average fiber fixation, paraffin versus fresh frozen, there are a num-
areas were approximately 2,000 }lm 2 with those in the ber of difficulties associated with the assessment of
leg muscles being larger than those of the arm muscles. the cross-sectional area of skeletal muscle fibers (183,
Nevertheless during skeletal growth the longitudinal 326, 637, 662). First is that once removed from the
growth of the muscle fibers is such that the average intact muscle there-is usually a shortening of the fibers
sarcomere length in the mature muscle fibers is not (363). In fresh-frozen sections, sarcomere length aver-
markedly different from that of the young animal (122, ages 2.0 }lID (range 1.8-2.2 }lm) (320, 520). This con-
252). trasts with 2.8 urn in the stretched state (520). Simi-
Colling-Saltin (123-125, 697) has examined muscu- larly, Holly et al. (359) observed a 25% reduction in
lar growth in the lateral portion of the quadriceps, the length of a muscle after removal from its skeletal
rectus abdominis, deltoid, biceps brachii, soleus, and attachments. This results in an overestimate of 33% in
gastrocnemius muscle of 86 fetuses and 50 infants and the fiber area. Moreover several methods can be ap-
children to age 7. The fetal samples included material plied in the actual determination of the area, which
from as early as 12-14 wk of gestation. The majority can also influence the results. The method used is
582 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

.
Lower Limb Muscles

~
20
N
0 o
JC
o
N
E 16
~
r:: r
0
...
Gl
ex 12
...

Gl
~
o
u,
8 0- Vastus Lateralis
Gl
CI'
- Gastrocnemius
...
0
Gl
>
ex f
- Rectus Femoris
FIG. 16. Data are for muscle from 4
human subjects ranging in age from
2 mo to 18 yr. Fiber areas for infants
less than 1 yr are not plotted. A:

relationship between age and muscle
fiber cross-sectional area in the lower
o
limb muscles of humans. Equation of
the regression line y = 115 + 111x.
o 4 8 12 16 20
Between age and fiber area r = 0.92; Age in Years
between age and body height r =
0.98. B: relationship between age and B
muscle fiber cross-sectional area in Upper Limb Muscles
the upper limb muscles of humans.
(\/
Equation of the regression line is y
= 112 + 56x. Between age and fiber ~16
area r = 0.85 [Data from Aherne et
al. (2).]
)(

(\/
E
~ o
.:12
0
Q)
o
o
~

<t o
~
Q) 8

..Q
u,
Q)
01
0
~
Q) 4 o Deltoid
>
<t
- Biceps Brachii

o
o 4 8 12 16 20
Age in Years
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 583

.,. .,.
100 tmrmnnmmTTTrmmT'i'i'n:::;:;;::;:;:;:::=:=:===~===-=----~~100
----------
ST

Undifferentiated

12 15 20 25 30 35 40 42 4weeks lyea r
Gestation P Age
FIG. 17. A summary description of the relative occurrence of various fiber types in human skeletal
muscle during gestation and 1st year of life. The slow-twitch (ST) fibers are divided by size with the
small fraction ofWoWfart's B fiber above the dashed line (725). [Data from Colling-Saltin (123, 125).]

usually one of the following: 1) direct measurement by examination of the muscle sections in the late stages
planimetry,2) analysis by a grid technique (or particle of fetal life did not reveal any evidence of mitotic
size analysis), and 3) assessment of the shortest di- activity or of fibers undergoing "longitudinal split-
ameter and estimation of cross-sectional area from the ting." On this basis Montgomery concluded that the
assumption that the fibers are circular. The validity of apparent increase in fiber number of the sartorius
these methods has been discussed by Edstrom and muscle of man during later fetal and early postnatal
Torlegard (178), Aniansson et al. (11), and Song et al. life was the result of a longitudinal fiber growth such
(649). Because of its ease of application one of the that more fibers appeared in the histological cross
most frequently used methods for estimating the cross- section. The mechanisms for such a longitudinal and
sectional area of the fibers is measuring the least circumferential growth through the addition of sarco-
diameter. The method is valid if the fiber area is meres on the distal ends of the fibers and myofibrils
circular, which appears to be the case in fetal and has been discussed in the chapter by Goldspink in this
infant skeletal muscle. However, with increasing age Handbook. The lack of increase in fiber number in the
the fiber areas become less round and the result is a sartorius muscle is in agreement with the observation
consistent underestimate of the fiber area. This situ- that there is no evidence of fiber division in the biceps
ation is illustrated in Figure 18, where it is evident brachialis muscle of man after midgestation. Moreover
that as the fibers become larger there is a progressive no myoblasts have been observed in the muscle of
deviation from the line of identity. This method can human beings after birth, and the number of fibers in
be used if an appropriate correction factor is employed. the biceps of infants is similar to that of adults (115,
Postnatal increases in muscle size are closely asso- 344,520).
ciated with hypertrophy of the preexisting fibers (e.g.,
see POSTNATAL DEVELOPMENT, p. 580). Data on the USE AND DISUSE. Muscular strength. Heavy-resis-
number of fibers in human skeletal muscle come pri- tance exercise results in increases in muscle bulk in
marily from studies of the sartorius muscle as reported excess of that which occurs during normal growth and
by MacCallum (470) and Montgomery (496). Mac- development. This is exemplified by the conspicuous
Callum made fiber counts from cross sections of five musculature of persons who engage in heavy physical
fetuses and one full-term infant and concluded that labor or in athletic events where heavy-resistance
fiber number was established before birth. Montgom- exercise is practiced (body building). The importance
ery employed similar methods to estimate the total of the increase in size in response to functional over-
number of fibers in the sartorius muscle from samples loads lies in the fact that the strength of a muscle is
including three stillborn (two fetal and one full-term) closely related to its cross-sectional area (381, 382,
infants, two well-nourished infants (4 and 13 mo old), 520). This principle is based on the concept that all
and two adults (64 and 74 yr old) of unspecified sex. motor units are maximally activated during MVC (181,
The number of fibers appearing in the cross section of 643). Moreover there was little difference in the
the 4-mo-old infant was about twice that observed for strength per square centimeter among boys, sedentary
the 32-wk-old fetus. There were no major differences males, and highly trained judo athletes (381, 382). This
in total fiber number with advanced age. Histological supports the general contention that the capacity of
584 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

J,lm2

16.000

14.000

12.000

nl
...
CIJ
nl
_10.000
nl
FIG. 18. Relationship between cross-sectional fiber
c
area and lesser diameter in human skeletal muscle during
gestation and 1st years of life (small graph), and adults ...
o

(large graph). [Small graph from Colling-Saltin (123); U
large graph from Sjegaard (641).] CIJ
III 8.000
III
III
...o
..,
2
....m Fibrearea
()
U 000
-before partU$
6.000
400 oafter "

300

200
4.000
.:
A:.~ .
'00

- --+--------+------+------t-
5 10 15 20 25 P
Fib,ediameter

2.000
;<
30 40 50 60 70 80 90 100 110)Jm
The lesser d i a met er

muscle to develop force per unit of cross-sectional area trained arms of these subjects increased in strength by
is constant. If one accepts the concept that all individ- 30% without any change in cross-sectional area of the
uals can maximally activate all motor units in a muscle muscles.
(55), it is difficult to explain the increases in force- Fiber cross-sectional area. There are several re-
developing capacity that occur in the nontrained limbs ports in which the cross-sectional area of the fibers in
of individuals who train a contralateral limb or in skeletal muscle of weight lifters or those who have
instances where the training does not produce in- engaged in a variety of sports events have been ex-
creases in the cross-sectional area of a muscle (443, amined (see Table 9). The general conclusion from
689). Such changes in the force-developing capacity such studies has been that weight lifters generally
may be a function of the central nervous system rather have larger fiber areas than sedentary individuals or
than of the muscle (493). Moreover isometric training those who engage in endurance-type activities (261).
consisting of three maximal contractions sustained for Edstrom and Ekblom (175), Costill et al. (129), and
10 s and separated by 1 min of rest continued for 100 MacDougall and co-workers (471,472) have reported
days has been reported to produce a near doubling of that a period of strength training results in increases
the volitional strength of the forearm flexor muscles in the cross-sectional area of the FT fibers. Thorstens-
(399). This increase occurs with only a 23% increase in son et al. (689), however, did not observe a similar
the cross-sectional area of the muscles. The non- finding in subjects who had participated in 8 wk of
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 585

strength training. In the latter study this was true in return to normal physical activity there is a return of
spite of an increased muscle mass and total body fiber size to normal (255).
potassium. Muscle mass increased by only 1 kg (2.5%), The nutritional status of the animal can also influ-
however, which is probably too little to detect in fiber ence the rate and magnitude of the growth of muscle
size if the increase is not confined to only a few muscle fibers (250, 251, 309, 321, 424). In one case it was
groups. Gollnick, Saltin, et al. (260) did observe a reported that a short period of complete starvation of
selective enlargement of ST fibers after a 6-mo endur- young (weanling) rats resulted in an approximately
ance-training program. MacDougall et al. (471, 472) 20% loss of fiber number in the skeletal muscles. In
have also examined the effect of weight-lifting activi- starved and refed rats the number of fibers was normal
ties on the cross-sectional area of the fibers in the (321). These data are questionable, however, since the
triceps muscle of man and found muscle-fiber hyper- changes reported in muscle weight, fiber diameter, and
trophy. fiber number are such that to accommodate the overall
Forced inactivity, for example, after injury, reduces changes there would have had to have been an elon-
the cross-sectional area of the fibers in skeletal muscle gation of the fibers during starvation and a subsequent
(301,471,578). Subjects whose legs are immobilized in shortening with refeeding. These data appear to be
fixed casts as a result of radical knee surgery readily limited by an accurate determination of total fiber
demonstrate this phenomenon (299). In these subjects number.
the cross-sectional area of the fibers was similar in the
normal and the injured leg prior to surgery. After a 5- HYPERTROPHY VERSUS HYPERPLASIA. There has been
wk immobilization there was a 27% decline in the considerable interest over the years in the mecha-
cross-sectional area of the ST fibers of the vastus nism(s) by which skeletal muscles increase in size in
lateralis muscle. There was, however, no change in the response to heavy-resistance exercise. The early stud-
area of FT fibers. Data are also available from subjects ies of Morpurgo (500, 501) where increases in muscle
whose one leg had been immobilized for 15 wk as a weight produced by training did not alter the number
result of fracture (607). Such immobilizations did not of fibers contained in the cross section of the sartorius
alter the composition of the muscle in terms of the muscle of the dog (one muscle having been removed
percentages of the different fiber types. However, the before and the other after training) have been the
cross-sectional area of both ST and FT fibers was cornerstone of evidence that muscular growth in re-
lower by an average of 47% and 38%, respectively. The sponse to functional overloads occurs by hypertrophy
reduced FT fiber area after a 15-wk immobilization as of the fibers and not by hyperplasia. Subsequent stud-
opposed to no change after a 5-wk immobilization is ies (624, 655, 685) supported this general concept.
probably attributable to the fact that in the latter There is also general agreement with the concept that
study the patients were encouraged to perform inten- normal growth of muscle occurs by hypertrophy of the
sive isometric contractions of the thigh. With such fibers present in the muscle at birth.
contractions FT fibers are recruited, and this may be The concept of a postnatal growth of muscle occur-
an adequate stimulus for maintaining normal size of ring by a combination of longitudinal and circumfer-
the FT fibers. This was evident from the relatively ential hypertrophy of the preexisting fibers has re-
large FT fibers in these patients. When such exercise cently been challenged by reports of larger numbers
is not performed, the FT fibers also become smaller of fibers in enlarged muscle as compared to control
after a 4- to 6-wk period of inactivity induced by muscle (276,280,379,593,609,610,612,648, 704, 731).
putting a cast on the leg (299). In some cases the suggestion has been made that the
The effect of physical conditioning on the fiber size increase in fiber number was the result of new fibers
of a normal leg and a leg after 6-8 wk of immobilization formed by a longitudinal division of preexisting fibers
has also been examined (301). In these experiments (168, 303-305, 573, 593, 612, 648, 668, 701, 704, 731).
computerized tomography was used to establish the This suggestion is based in part on the observation
total cross section of the thigh muscles. These exper- that fibers with points of branching or with central
iments have firmly established an atrophy of the thigh cleavages exist in skeletal muscle (172, 280, 390, 573,
muscles as a result of chronic immobilization. This 612, 614, 622, 668). It should be pointed out that the
atrophy was almost exclusively restricted to the knee existence of such fibers in skeletal muscle was reported
extensors, whereas the hamstring muscles were almost in 1866 by Eulenberg and Cohnheim (207) and in 1891
unchanged (301). Moreover the relative changes in the by Erb (194). The major impetus for espousing the
knee extensor cross section and fiber size were closely concept that increases in fiber number occur as a
correlated. A similar conclusion was reached by Ren- result of fiber division (a so-called fiber splitting) dur-
strom in his study of the knee extensors in below-the- ing muscular enlargement produced by functional
knee amputees (578). In these investigations the total overload came from the studies of Van Linge (701)
cross-sectional area was reduced by 30% and that of and Reitsma (573). These investigators produced mus-
the fibers by 26%. cular enlargement in the hindlimb muscles of the rat
In animals there is also an increase in fiber area of by either denervation or surgical ablation of synergis-
muscle exposed to overloads (248, 254, 255). With a tic muscles. In some cases exercise was used in com-
586 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

bination with inactivation of a synergist to produce by hanging a weight on one wing (648). However, in
further muscular enlargement. Van Linge (701) ob- another study the increased cross-sectional area of the
served what were considered to be new fibers in his- fibers in the enlarged muscles of the shoulder of
tological sections of the overloaded, enlarged muscles. chicken, where growth was induced by a chronic
These "new fibers" were described as small fibers stretch, could account for the observed greater muscle
interspersed among normal-sized fibers. It was sug- weight (359).
gested that these represented "young muscle fibers, Schiaffino et al. (612) surgically removed the tibialis
the growth of which was stimulated by strenuous anterior muscle of 1- to 65-day-old rats. At time inter-
training." Technical difficulties were cited by Van vals ranging from 4 to 76 wk postsurgery, the remain-
Linge as making it impossible to count all of the fibers ing extensor digitorum longus muscles were on an
in the muscle from histological cross sections. Subse- average 32% heavier, and cross sections contained 25%
quently Reitsma (573) reported the existence of similar more fibers than the contralateral control muscles.
small fibers in histological cross section of experimen- The presence of fibers with branches in those teased
tally enlarged muscle. Moreover when enlarged mus- from nitric acid-treated muscles was used as evidence
cles were digested in nitric acid and fibers teased free, for proliferation of fibers via splitting.
some fibers with branches and appendages of varying Ianuzzo, Gollnick, et al. (379) reported the existence
length were isolated. The presence of such fibers was of 30% more fibers in the cross sections of the plantaris
interpreted as evidence that a longitudinal splitting of muscle of rats where a doubling of its weight was
the fibers was occurring. Unfortunately the total num- induced by the surgical removal of the gastrocnemius
ber of fibers in the muscles was not determined nor muscle. The cross-sectional areas of the major fiber
was the frequency of the branched fibers established. types in the muscles had increased from 30% to 60%.
Little is known about the number of fibers in human In this study there was no change in the fiber number
skeletal muscle. Etemadi and Hosseini (205) reported in the soleus muscle in spite of a 45% increase in its
that the number of fibers in the human biceps brachii weight. No evidence of fiber branching was observed
muscle was larger in an athletic subject (316,243 from the histological observation of the sections used
fibers) as compared to two sedentary individuals to determine fiber numbers.
(227,233 and 199,240 fibers). Ofthese subjects, the one Gonyea and associates (276, 279, 280) trained cats
with well-developed musculature also had the greater to perform a weight-lifting type of activity to produce
fiber diameter (45.25 /lm as compared to about 23 /lm muscular enlargement. This experimental procedure
for the sedentary individuals). The difference in fiber was claimed to be a more physiological method for
size is similar between large and small breeds of dogs producing muscular growth than the denervation or
(413). surgical removal of synergistic muscle. Differences in
The total number of fibers in the human biceps has weight of from 6% to 16% between the flexor carpi
been estimated from measurements of the total cross- radialis muscles of the control and experimental legs
sectional area of the muscle determined by comput- were produced by this procedure. The enlarged mus-
erized tomography and the area of the individual fibers cles were reported to contain an average of up to 20%
determined from biopsy samples (519, 521), assuming more muscle fibers, and the average fiber diameters
that the majority of the fibers extend through the were 9%-15% larger than those of the contralateral
whole muscle (623). In sedentary male and female control muscles. Fiber number was assessed from a
subjects the cross-sectional area of the muscle aver- histological cross section made at the point of greatest
aged 11.6 em" (range: 9.8-16.1) and 8.7 em" (6.8-10.6), girth of muscle belly. The identification of fibers in
respectively. These values were 12.3 em" (11.9-12.9) serial sections with branch points was cited as evi-
and 9.0 em" (7.7-9.7) for trained male and female dence of fiber splitting. However, there was no evi-
swimmers. The total number of fibers in the biceps dence of the frequency of this phenomenon. To pro-
averaged 280,000 (280,000-290,000) and 420,000 duce a 20% increase it would have had to occur in
(340,000-500,000) for the sedentary female and male every fifth fiber. Even if one accounts for the time it
subjects as compared to 320,000 (240,000-380,000) and takes to induce the change, split fibers would have to
350,000 (280,000-400,000) for the trained female and occur at a very high rate.
male subjects. These data demonstrate the existence The number of fibers in the plantaris muscle has
of considerable variation between the fiber number of been reported to decline between the ages of 6 and 45
subjects and considerable overlap between the sexes wk in sedentary but not in trained guinea pigs (213,
and the sedentary and trained groups. There is no 214). Termination of training resulted in a progressive
evidence of a systematic difference between the sed- loss of fibers. This suggested that a normal attrition of
entary and the trained groups, the greater total cross- fibers occurs, which could be prevented by physical
sectional area of the muscle being attributable to the activity. In a subsequent paper (481), however, a math-
larger cross-sectional area of the individual fibers. ematical model, based on changes in fiber angles with
A greater number of fibers in the cross section of growth, was described to demonstrate that the deter-
the anterior latissimus dorsi muscle has also been mination of fiber number from counts made of histo-
reported for chicken where enlargement was produced logical cross sections was invalid for penniform mus-
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 587

cles. On this basis it was suggested that the earlier dence of branched fibers was similar for normal and
data were in error. enlarged muscles. However, the observation that
The tedious nature of isolating all of the fibers of a points of branching can occur anywhere along the
muscle has deterred the application of this method to length of the fiber illustrates the technical difficulty of
the study of normal growth and development and of using histological cross sections to evaluate its fre-
hypertrophy versus hyperplasia during work-induced quency (275, 303-305, 573, 612). The appearance of
muscular enlargement. Gollnick and co-workers (275) branched fibers in all muscles was interpreted as an
dissected, counted, and examined each fiber over its indication that these abnormal fibers are normally
entire length for bifurcations. In these studies there present in small percentages and do not represent an
was no change in fiber number in enlarged as com- active process of a longitudinal division of fibers.
pared to control skeletal muscle in the rat. Muscular The finding of Gollnick et al. (275) supports the
enlargement ranging from 10% to 115% was induced in older concept that the number of fibers in skeletal
the penniform plantaris and extensor digitorum longus muscle is established early in life (188, 470, 496, 624,
and in the parallel-fibered soleus muscle by surgical 712) and that the exceptional enlargement that occurs
ablation of a synergist and treadmill exercise. Muscles in response to a variety of overloads is a true hyper-
were examined from 4 to 40 wk after the ablation of trophy. This supports the conclusion of Hall-Craggs
the synergistic muscle. Treadmill running was for 6-8 and co-workers (303-305) and of James (394) that if a
wk and was initiated at least 4 wk (18, 378) after the splitting of fibers in skeletal muscle does occur during
surgical removal of the synergistic muscle. Although enlargement, it is of minimal importance in the overall
considerable variation in the number of fibers per increase in muscular size. Moreover James concluded
muscle existed among animals, the total fiber number from the changes in fiber cross-sectional area during
in the same muscle from the right and left leg was hypertrophy of the mouse extensor digitorum longus
similar regardless of whether it was normal or enlarged muscle that a hypoplasia of fibers must have occurred
(Fig. 19). It should be pointed out that considerable (395).
variation exists among animals for the total number There are reports of increases in the DNA content
of fibers for the same muscle (Fig. 20). The differences of skeletal muscle during normal growth and work-
in dry weight of individual fibers of the enlarged induced hypertrophy (307, 368, 499). This could be
muscle as compared to those from the normal muscle interpreted as an indication of the addition of new
demonstrated that the increase in weight was the fibers. However, the bulk of the increase in DNA
result of hypertrophy and not hyperplasia. The inci- arises from the addition of connective tissue to support
enlarged fibers (18, 393). Part of the increase in DNA
Fiber No. In is associated with a proliferation of the satellite cells
Thou.and. PLANTARIS MUSCLE of muscle (3, 502, 503, 610, 611, 615, 616, 628). Some of
these are apparently incorporated into the existing
14 muscle fibers. This has been proposed as a mechanism
whereby the ratio of nuclear material to other cellular
13
components is maintained at a constant level within
the cell. Of some interest is the observation that block-
ing DNA synthesis does not stop the hypertrophy of
muscle fibers in the rat soleus muscle after tenotomy
.,....
12
...J
of the synergists (225). This did completely inhibit
connective tissue proliferation: an almost complete
;; II
lack of new nuclei was observed in histological sec-
.,
C
tions.
E
.,
~
10 Since there has been a rather wide acceptance of
Do the concept that the total number of fibers in skeletal
'"
1&1
muscle can increase with work-induced growth, it
9 seems appropriate to comment on the methodology
that was used to arrive at this conclusion. Basically
there are three methods that are used to determine
total fiber number in skeletal muscle. These are: 1)
counting all fibers that appear in a cross-sectional cut
I ,
of the muscle; 2) counting the fibers in a given cross-
9 10 II 12 13 14
Control Lev sectional area cut and then estimating total fiber num-
ber by an extrapolation to the total area of the section;
FIG. 19. Comparison of the number of fibers in a control and
enlarged plantaris muscle of the rat. Muscular enlargement was
and 3) making a cross-sectional cut, dispersing the
induced either by ablation of the gastrocnemius muscle (el or a fibers in saline, and counting the fragments with an
combination of ablation of the gastrocnemius muscle and treadmill electronic device (684). All methods appear valid for
exercise (0). [From Gollnick et al. (275).] estimating the total number of fibers in the cross
588 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

PLANTARIS MUSCLE

14

.
13 C>


.
"e:
0
:::>
12


8



0 C>


0 0 C>


0
~ C>
l- C>

: e.
e: C>

..
C>

eP
II
~
0
C>
C>
.&J
0


E
:::>
z 10
..
~




0
0 0
0 o


.&J
LL 9 0

I0 ,
100 200 300 400 500 600 700
Muscle Weight in mg

FIG. 20. A plot of the number of fibers vs. total wet weight for the plantaris muscles. e, Control
muscles (including normal weanling, sham-operated, thyroidectomized, and control muscles from
experimental animals); 0, muscles enlarged by ablation of the gastrocnemius muscle; and (), muscles
enlarged by ablation of the gastrocnemius muscle and exercise. The smallest muscle weighed 25 mg
and the heaviest 712 mg. [From Gollnick et al. (275).]

section of muscle. However, these methods assume form fiber arrangements where fiber number was de-
that all of the fibers in a muscle are either contained termined from histological cross sections, these data
in the cross section or that changes in the number of are open to doubt. Also the estimation of the size of
fibers contained in the single section are representa- the fibers depends on the ability to section the muscle
tive of any change in the entire muscle. These as- perpendicular to the long axis of the fibers. When the
sumptions appear to be tenable only when the fibers cuts are made at a tangent to the long axis of the fiber
lie parallel to the long axis of the muscle and traverse the area and diameter will be overestimated.
the point where the cross section is made. This, how- The difficulty in determining the fiber number in a
ever, is not the case for muscles where the fiber muscle with a multipennate fiber arrangement is illus-
arrangement is penniform. The problem with deter- trated from the studies of Gollnick and associates
mining the total fiber number in muscles with pennate (275) and of Gonyea et al. (276, 280). Gonyea et al.
fiber arrangement has been discussed by Clark (117) reported that the flexor carpi radialis muscle of the cat
and alluded to by others (478,490,571,704). In muscles contained about 7,500 fibers as estimated from a cross
with a single pennate fiber arrangement all fibers could section made at the point of greatest girth. When this
be included in carefully spaced, multiple cross-sec- muscle was treated in a manner that permitted isola-
tional cuts. With multipennate fiber arrangements the tion of each fiber it was found to contain about 28,000
problem is greatly compounded. It cannot be assumed fibers (275). Similarly, Schiaffino et al. (612) estimated
that a cross-sectional cut made through the same point the number of fibers from cross sections of the extensor
of the muscle, for example, the point of greatest girth, digitorum longus to be about 3,400. When counted
includes the same number of fibers of a normal versus directly this muscle, with a single pennate fiber ar-
an enlarged muscle since this depends on the angle rangement, was found to contain about 5,200 fibers.
that the fibers form with the longitudinal axis of the
muscle (275). This fiber angle is known to change SUMMARY. From birth to full maturity there is an
during muscular enlargement (57, 309, 490). A change increase in muscle weight of from 100- to 200-fold in
in fiber angle in the mature animal is necessary to the skeletal muscle of most mammals. This increased
accommodate the larger fiber diameter without any muscle size is the result of a longitudinal growth
change in the total length of the muscle. Since in- produced by the addition of sarcomeres to the ends of
creases in fiber number with work-induced growth the existing muscle fibers and by circumferential
have been reported primarily for muscle with penni- growth produced by the addition of myofibrils. During
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 589

the growth process the total number of nuclei in- level. Only a few studies are available dealing with the
creases such that the ratio between cellular material effects of immobilization or termination of training on
and nuclei remains rather constant. With added phys- the phosphagen stores of muscle. Studies with animals
ical demands, such as heavy manual labor or weight suggest that although there may be increases in the
lifting, there is an additional increase in muscle mass. phosphagen stores after training (228, 534), these mod-
This increased muscle mass is produced by further ifications are small and probably biologically unim-
increases in total cross-sectional area of the individual portant. Further proof that changes in the immedi-
fibers and not by the addition of more muscle fibers. ately available energy stores of ATP and CP are not
With disuse or with inadequate nutrition there is a important features of adaptation to training comes
loss of muscle mass as a result of a decrease in cross- from observations of elite athletes. In these individu-
sectional area. als, whether they have trained for strength develop-
ment or for endurance, the ATP and CP concentra-
Metabolic Capacity tions in the muscles do not differ more than a few
POSTNATAL DEVELOPMENT. The skeletal muscle ofthe
moles per kilogram wet weight (-10%) from that of
newborn contains substrate concentrations and en- sedentary individuals. Attempts have been made to
zyme activities that are only slightly below those found determine whether differences exist between the ST
in later life when these are expressed per unit dry and FT fibers (375). In these studies the ATP and CP
weight (124). This could be interpreted as indicating concentrations were found to be slightly higher in the
that parallel increases occur in all muscular compo- ST as compared to FT fibers in the muscle of female
nents with postnatal maturation. However, with athletes competing in endurance events (312).
growth there is a continued differentiation of the fiber Glycogen. In the first studies on the glycogen stores
types that necessitates a preferential synthesis of of human skeletal muscle where the influence of ex-
either mitochondrial, cytoplasmic, or myofibrillar ercise was examined, it was noted that higher values
proteins depending on the type of fiber that develops. existed in trained than in sedentary individuals (341).
This is illustrated by the observation that at birth Thereafter several studies, both longitudinal and
histochemical staining for NADH-tetrazolium re- cross-sectional, demonstrated that subjects undergo-
ductase and a-glycerophosphate dehydrogenase ing strength-, sprint-, or endurance-training programs
(aGPDH) does not discriminate between fiber types possessed larger muscle glycogen stores (260, 373, 418,
(714). In the skeletal muscle of adults these histochem- 472), although in some instances the difference be-
ical procedures identify major differences in the met- tween the trained and sedentary state was small. Con-
abolic profiles of the fibers (35, 540). Based on dry versely immobilization or detraining results in a re-
weight measure the increase in end-terminal oxidation duction in the glycogen concentration of skeletal mus-
enzymes of the mitochondria does not parallel that of cle (299). The changes observed with activity and
the contractile proteins in all fibers (627). This has inactivity are, however, well within the more dramatic
been illustrated in mixed-fiber skeletal muscle where variation in the glycogen concentration of skeletal
the checkerboard appearance of the muscle only ap- muscle that can be induced with dietary manipulations
pears with maturation (249,253,524,695). The loss of with or without exercise (51, 271, 396, 397, 560). The
mitochondrial density in the FT b fibers appears to be one-leg model, that is where one leg is trained and the
a function of a preferential production of myofibrillar other left untrained, has been useful to assess objec-
proteins. This growth effect can be modified by en- tively the quantitative effect of exercise, divorced from
durance training (4). either dietary or hormonal influences, on muscle gly-
How this differential growth is regulated is un- cogen stores. At least three (333, 559, 603) such studies
known. Since it is the rule rather than the exception, are available where the vastus lateralis muscle of a
different stimuli and regulatory mechanisms must be control and an endurance-trained leg was examined.
present for the increases in contractile proteins and In these studies the glycogen concentration of the
metabolic enzymes. Evidence suggests that this is trained leg was from 6 to 60 mmol/kg wet wt higher
regulated, at least in part, by the motor nerve (83,323, than that of the untrained leg. An alternative approach
334,371,465, 525-527, 544, 551, 567). to this problem has been to examine the glycogen
content in the arm and leg muscles of individuals
USE AND DISUSE. Phosphagen stores. There are re- whose training is primarily with either the arms or the
ports of increases and of no change in the ATP and legs, for example, bicyclists, canoeists, and swimmers.
CP concentrations of human skeletal muscle with Such studies have revealed that the muscle glycogen
either endurance or strength training (195, 415, 418, content is higher in the trained than in the control
472). Increases in both ATP and CP concentrations muscles with differences varying from 20 to 101 mmol/
have been reported in the limb muscles of adolescent kg wet wt. Training increases glycogen synthase activ-
(195) and adult (415, 418) males after programs of ity (95, 365, 366, 497, 559, 624, 675, 682). When activi-
endurance training. However, when the training was ties of hexokinase and glycogen synthase were also
extended from 3 to 6 mo in the adult group, the ATP compared in the two legs where only one leg was
and CP concentrations returned to the pretraining trained (559), both enzymes were found to be increased
590 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

in the trained leg with the relative increments being skeletal muscle. There are reports of a decline in the
about 30%-50%. The muscle glycogen concentrations triglyceride content of skeletal muscle of man with
in these studies were also increased from 38 to 50 exercise (234).
mmol/kg wet wt. These differences represented rela- The triglyceride content of both the red and white
tive increases of 47%-100%. portion of the gastrocnemius muscle of the rat has
Although results vary, endurance training appears been reported to be reduced by training (232, 235).
to increase the glycogen stores of rat skeletal muscle Data are also available, however, suggesting that en-
(25, 268, 273, 672). The magnitude of the increases durance exercise does (231, 232, 282, 572, 658) and does
varies from about 25% to 70%. There are, however, not alter (27, 282, 658) the triglyceride stores in the
reports of no difference in the glycogen concentration different skeletal muscle fiber types in the rat.
of skeletal muscle of trained as compared with seden- Glycolytic enzymes. The number of longitudinal
tary rats (674). Moreover this increase in glycogen training studies focusing on changes in the activities
appears to be localized, occurring in some muscles but of glycolytic enzymes in human skeletal muscle is
not others after endurance training (25, 268, 672). This limited. When these studies are divided into reports
cannot be attributed to a specific use of the gastroc- concentrating on improving strength, speed (sprint-
nemius muscle since swimming results in a large re- ing), or endurance capacity, only one, or at the most
duction in the glycogen content of all hindlimb muscles two, reports are available in each area. Although this
(572,679). Sprint training has no effect on the glycogen is the case, the adaptive response of the glycolytic
concentration of any of the fiber types found in rat enzymes in skeletal muscle to varying patterns of
hindlimb muscle (608). increased use is rather clear. Training regimens de-
Triglyceride stores. Few studies have measured the signed to increase maximal strength have not pro-
triglyceride concentration in human skeletal muscle, duced alterations in the activities of PHOS, PFK, or
and of these, only three were longitudinal with meas- LDH (129, 443). This is true both for dynamic and
urements made on the same subjects before and after static exercise. The response of muscle appears to be
training (104, 333, 498). Quantitative morphometric related to the total duration of the exercise. Thus no
techniques applied to electron micrographs have dem- changes were noted in muscle when the resistance was
onstrated that the lipid content in muscles of seden- so high that the total number of repetitions to exhaus-
tary man varies between 0.1 and 0.6 vol% depending tion was completed in 6 s (129). When the resistance
on the muscle examined (364, 422, 423). In muscle was lowered and the exercise extended to 30 s, how-
from trained subjects the range for the same muscles ever, there was a 10%-20% elevation in PHOS and
was from 0.2-0.8 vol%. Strength and endurance train- PFK activities but LDH was unchanged. A high-inten-
ing altered the triglyceride content of muscle. Morgan sity endurance training did produce an increase in
et al. (497, 498) and Bylund-Fellenius et al. (104) PFK activity (195, 260). Hexokinase also has been
observed elevation in the triglyceride content of the reported to be elevated with training (497).
quadriceps muscle after endurance training. The in- Further information concerning the adaptive re-
crease was about 50% from an initial value of approx- sponse of the glycolytic system comes from cross-
imately 10 pmol/g wet wt. Of special interest, however, sectional studies of athletes competing in typical
are results from a study where subjects trained only strength and sprint-type events. Shot-putters, weight
one leg thereby permitting comparison with the non- lifters, and discus throwers have PHOS, PFK, and
trained leg to obviate the effects of diet. In this in- LDH activities well within the range of sedentary
stance there was no difference in triglyceride content subjects (130, 261), whereas sprinters, jumpers, and
of the muscles of the two legs (333). Variations in the runners (400-800 m) usually have elevated levels of
percent of lipid in the diet is a major factor contrib- these enzymes (130).
uting to the fluctuation in the triglyceride stores of The influence of sprint and endurance training on
skeletal muscle (396). Jansson and Sylven (396, 400) total LDH activity and on the isozymes of LDH has
found that after 5 days of consuming a fat-enriched been examined (638, 639). Cross-sectional comparisons
diet (70% fat, 5% protein, 8 rn.I/day), the triglyceride were also made between weight lifters and endurance
content of the quadriceps was 22 umol/g wet wt, and athletes (419, 638, 683, 688, 689). Total LDH activity
the same after consumption of a low-fat diet (10% fat, was not altered by sprint training. These results and
20% protein, 8 m.L'day). The problem of whether also the report of high values in the muscles of weight
physical training has a significant effect on the muscle lifters (419, 638) contrast to some mentioned above. It
triglyceride content can also be examined from cross- has been found that the muscle of sprint-trained in-
sectional studies. When data from several studies in dividuals contains a relatively high percent ofLDH 4 _ 5 ,
which the same methods were used are pooled, there whereas muscle from endurance-trained individuals is
is a slight tendency for higher muscle triglyceride especially high in LDH l _ 2 (638). Part of the explana-
stores in the most highly trained individuals (B. Essen, tion for the differences between athletic groups may
personal communication). The variation is, however, lie in the fiber composition of the muscle. Thus it is
large. Thus factors other than physical activity may known that ST fibers show not only lower LDH activ-
dominate in determining the triglyceride content of ities but also have high percentages of LDH l _ 2 (638,
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 591

683). The type and cellular location of the LDH is also been used to study high-intensity training (345). One
different for the fiber types and could be an important bout consisted of six sprints, which were repeated
factor in their function (210, 211, 259, 416, 542, 702). eight times with 2.5-min rest periods between bouts.
Clearly in future studies where adaptations of LDH An endurance program of running 12.5 min at 35 m/
are investigated, close attention must be given to the min was also studied. Activities of phosphoglucomu-
nature of the muscle sample that is analyzed. tase (PGM), LDH, and phosphoglucoisomerase (PGI)
How varying types and intensities of physical activ- were determined in the soleus, plantaris, and white
ity influence the activities of enzymes of the Embden- portion of the gastrocnemius muscle after 8-16 wk of
Meyerhof pathway in rat skeletal muscle has been training. Small but statistically significant reductions
described in numerous reports (see ref. 265). There in the LDH activities of the soleus and white portion
appear to be two major problems with many of these of the gastrocnemius muscles were reported after 8 wk
investigations: 1) the exercise used for training was of sprint training.i The activity of PGI was higher in
often of insufficient intensity to place significant de- the plantaris but lower in the white gastrocnemius
mands on this system, and 2) in many cases the muscles, whereas LDH and PGM were both lower in
enzymes assayed were not those generally considered the soleus muscle after endurance training. After 16
to be rate limiting or regulatory. The earliest of these wk of training, LDH activity was lower in the soleus
used rather short periods of swimming as the mode of and white portion of the gastrocnemius muscle of the
exercise. The general finding was that this mild exer- endurance-trained group, whereas PGM was lower in
cise stress did not elicit any change in the activities of all muscles. In the soleus muscle of sprint-trained
PHOS, LDH, or aldolase (ALD) in the rat hindlimb animals, PGM activity was lower. Overall the magni-
muscles (264, 279, 283, 316, 318, 357). An exception tude of these changes was small but statistically sig-
was the early report of an increased LDH activity in nificant.
rat muscle after a program of swimming 1 min the first Of the enzymes normally considered glycolytic,
day and increasing the duration of the swim 1 min per hexokinase activity increases with endurance and
day for 30 days (729, 730). sprint training, as observed in rats (29, 659) and guinea
More strenuous programs of treadmill running (up pigs (38, 541). This increased activity appears to be
to 2 h) have been used to train rats. These have used related to changes in oxidative capacity of the muscle
speeds up to 31 m/rnin and in some cases have in- (29, 41, 137). Even in sedentary animals the highest
cluded periodic sprints at 42 m/rnin (353). Increases activities are found in the most oxidative enzymes.
in PFK, pyruvate kinase (PK), triosephosphatase de- Hexokinase activity is also many times lower than
hydrogenase (TPDH), and aGPDH of the soleus mus- that of other enzymes in the Embden-Meyerhof path-
cle and decreases in these enzymes as well as PHOS way. It responds rapidly, increasing shortly after the
have been reported in the red portion of the quadriceps onset of training and decreasing as quickly after ter-
muscle after such training programs (29). The activi- mination of a training program (38). Since hexokinase
ties of these enzymes were unchanged in the white is more involved with glucose transport across the cell
portion of the quadriceps. In the soleus, LDH activity membrane than in glycolysis, it cannot be considered
was unchanged, but it was lower in both the red and to be a glycolytic enzyme in the traditional sense.
white portions of the quadriceps muscle. The effect of Modifications in its activity appear to facilitate the
sprint training on the activities of select glycolytic uptake and oxidation of glucose from the blood.
enzymes has been reported (345, 608, 659). These Two points should be considered when evaluating
studies employed treadmill running with speeds up to the results of the experiments with rats. First, was the
99 m/rnin. In one study (659) the exercise was 45-s exercise severe enough to stress the glycolytic path-
bouts of running-two bouts in the morning and two way? Second, were the results influenced by the time
in the afternoon. At the end of a 3-wk training program at which the tissue samples were obtained after the
the running speed was 80 m/rnin. With the exception final training session? In the early experiments rats
of an increase in TPDH in the soleus muscle, there were exercised by swimming. The oxygen uptake of
were no differences in PHOS, TPDH, and LDH activ- the rat during swimming is about 4.6 ml.l00 g-l.
ities in the soleus and rectus femoris muscles 24 h min- 1 (19, 23, 484). This corresponds to less than 50%
after the final exercise session. In a second experiment, of V'02max for the rat (44, 78, 142, 629). This is below
training consisted of 18 alternate periods of 30 s of the exercise intensity that usually elicits an increase
exercise and 30 s of rest (608). The training program in the lactate concentration in the blood of man. The
covered 11 wk with the final running speed of 80 m/ lack of an increase in blood lactate of swimming rats
min attained during the 11th week. Activities of supports the contention that this is a mild metabolic
PHOS, PFK, and PK were unchanged in fast-twitch stress (257, 274). The rate of glycogen depletion and
muscle (both red and white), whereas for the slow- the increase in blood lactate that occur in the rat are
twitch soleus PHOS and PK activities were higher by functions of exercise intensity (19, 288). At running
70% and 35%, respectively. speeds below 22 m/rnin the lactate concentration of
An exercise program of 10 s of running (speeds up the blood is about 3 mM and glycogen breakdown
to 99 m/rnin) with 45 s of rest between bouts has also averages about 1.5 mmol.kg-1.min- 1. At running
592 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

speeds above about 25 m/rnin there is a sharp rise in for sprint exercise an increased demand on glycolysis
the lactate in the blood with a maximum of about 20 appears to cause adaptive changes in the glycolytic
mM having been observed at running speeds of about pathways. In the study where the largest increase in
70 m/min, At this point the rate of glycogen depletion PFK was observed after endurance training, histo-
was 20 mmol-kg v-rnin". These data support the chemical staining of tissue samples for aGPDH dem-
contention that for the high-intensity exercise used in onstrated an increased staining intensity of the FT
the sprint studies there is a significant substrate flux fibers with no apparent change in the ST fibers (260).
via the glycolytic pathway. With regard to the time of Chronic electrical stimulation of animal muscle via
obtaining the tissue samples after the final exercise the nerve has also been shown to alter the glycolytic
session, this varies from 1 to 3 days. This is an impor- capacity of skeletal muscle (323,550,553). In contrast,
tant consideration since the turnover rate of the gly- quantitative biochemical methods have failed to reveal
colytic enzymes lies between about one-half hour and any differences in the total PFK activity or in that of
a few days (154, 383, 544). An example of the impor- the individual muscle fiber types after endurance
tance of this is illustrated by the observation that a training in the rat (29, 337). Clearly further investiga-
period of prolonged exercise can increase the PFK tions regarding the adaptability of the glycolytic path-
activity of rat skeletal muscle (61). Since rats have way to varying types of training are needed.
usually been studied from 1 to 3 days after the last Mitochondrial enzymes. Though it has been known
exercise session, it is possible that the training effect for a long time that the capacity of muscle to consume
may have been totally or partially missed. Moreover oxygen was related to the level of activity of the citric
athletes are not usually studied at the point of peak acid cycle and electron-transport system, studies of
performance, and in training studies with man the adaptations in the mitochondrial enzymes of human
muscle samples may be obtained one to several days skeletal muscle were not undertaken until the late
after completion of the exercise. Because of these 1960s and early 1970s. At that time results over a
differing experimental protocols, the true extent of the period of time from cross-sectional studies of men and
adaptability of these enzymes in response to physical women performing physical activity of an endurance
activity may not be fully understood. type were published (6, 7, 10, 48, 103, 104, 130, 132,
Immobilization of the leg for from 1 to 6 wk did not 175,195,260,261,360,364,389,398,419,422,423,529-
produce any change in PFK activity (299). A similar 531, 559, 565, 566, 602-604, 639, 664, 703, 705). Cyto-
lack of change was observed with detraining (367). In chrome oxidase (CYTOX) and SDH activities were
the latter study PFK activity was similar to that of found to be elevated in the trained skeletal muscle.
sedentary subjects in the control phase for these Exercise designed to develop strength does not alter
groups. Inactivity produced by de nervation of rat skel- the activities of the mitochondrial enzymes (129, 261,
etal muscle results in a decline in the PK, ALD, and 471). When this type of exercise is practiced over a
LDH activities of the gastrocnemius muscle (316, 350) long time, it leads to a disproportionate proliferation
that is evident as early as 7 days after nerve section. of the contractile proteins, resulting in a dilution of
Thereafter a progressive decline in enzyme activities the mitochondrial concentration in the muscle fiber,
occurred until 8 wk after de nervation if activities were and the activities of the enzymes expressed per unit of
only 25%-38% of those of the control animals (350). muscle become lower than those of muscle from sed-
There were, however, no changes in the activities of entary individuals (261, 471). This situation is analo-
PK and ALD of the soleus muscle over the same gous to the growth dilution that occurs during the
period of time, whereas LDH had declined by 57%. early development in animals (249, 253).
There were also major histochemical changes (589). Sprint training, in contrast to high-resistance train-
These data support the concept that a differential ing, causes a definite adaptive response with signifi-
response to forced inactivity exists for the different cant elevation of the mitochondrial enzymes (603).
fiber types. When performed intermittently, thereby placing a se-
At first inspection there are conflicting reports of vere stress on oxygen utilization, isometric strength
the adaptive response of the glycolytic capacity of training also induces increases in mitochondrial en-
skeletal muscle to endurance training. Several reports zymes (291). Thus it appears that the concentration of
show no effect, whereas others observed substantial mitochondrial enzymes is increased whenever there is
increases. This apparent disparity may be due, at least a chronic demand for a high-oxygen consumption by
in part, to variations in the training protocols em- the muscle. In line with this is the finding that the
ployed. In studies where elevations in "\;02 max were largest increases in these enzymes occur after typical
induced by continuous strenuous but not maximal endurance-training programs (260,603). It appears to
exercise, glycolytic enzyme activities were unaltered make little difference whether the exercise is per-
(337). In contrast, in those experiments (196, 260) formed intermittently or continuously, although
where 50%-115% increases in PFK activities were ob- changes at the level of the individual fiber may be
served, the exercise was performed at or very close to affected (337). Other evidence for differences in the
"\;02 max, This probably resulted in a high demand for concentration of oxidative enzymes based on the rel-
pyruvate formation throughout the exercise. Likewise ative use of a muscle can be obtained from sedentary
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 593

individuals where the activities of the oxidative en- tions in arm muscles (261). Moreover training one limb
zymes for end-terminal oxidation are higher in the leg induces changes in the muscle of that limb but not in
than the arm muscles in spite of a similar fiber-type the muscle of the contralateral untrained limb (Fig.
distribution (261). The muscles of the legs are presum- 22).
ably used more in endurance activity than those of the The enzymes in the various metabolic pathways of
arms. the muscle cell are found in a rather constant ratio
The time course for the change in oxidative enzyme one to another (543, 546-549). The question arises as
activities and the concomitant change in whole-body to whether this constant proportionality is retained
V0 2 m a x (Fig. 21) suggests that there is a close relation- when adaptations occur in response to increased mus-
ship of these variables over the first 3-4 wk of training cular usage. This relationship does not appear to be
(6). Thereafter the increase in 'V0 2 m a x levels off, but disturbed in rabbit skeletal muscle in response to
the activity of the mitochondrial enzymes continues either normal physical activity, inactivity, or to
to rise. This disparity in the response of the V0 2 m a x chronic electrical stimulation (551, 553). Comparisons
and mitochondrial enzyme activities is further illus- of enzyme activities for terminal oxidation in the hind-
trated by comparisons of endurance athletes and sed- limb muscles of sedentary and trained rats also sup-
entary individuals. The V02 max of the athletes may be port this concept (142). Note, however, the finding of
twice that of the control subjects, whereas the activity a slightly smaller increase in mitochondrial protein
of the mitochondrial enzymes of the muscle is 3- to 4- than that observed for the citric acid cycle or respira-
fold higher than those of the sedentary individuals tory-chain enzymes (353-355, 495, 532). This may be
(605). As pointed out earlier, the adaptive response in due to the fact that some mitochondrial enzymes are
enzyme activity is local in nature. Competitive cyclists unchanged with muscular usage, for example, creatine
and endurance runners have higher activity levels for kinase, adenylate kinase, and aGPDH (355, 532). An
the mitochondrial enzymes in their legs than sedentary alternate explanation might be that the enlargement
individuals. Canoeists resemble sedentary people in of the mitochondria that occurs with endurance train-
their leg muscles but have elevated enzyme concentra- ing (268) alters the surface-to-volume ratio with

T
maximal Olyg.n uplak. ('~02 mal)
~
----
1
vUl.lat.SDH activity

",.~':~
_}_. .
.
-.; 140 .. <"oc""m. ,,"n ,
>
III ,

1 // I'\
r//
\
Cl
C
'c 130 ,,' /
~.'"

-...
ell /
\ '.

j~~-l
I
/V

-
III
~ 120
l/ 7-
,~/
o

u.
III
Cl
ell

\1 -. ,1.
C 110
III
...u
Ij
III ~ '.
Q..
,,~ I

100
,~

\',L-J.
L o 2 4 6 8
, ( !

.nd of
training
,
2
!

4 6
. ,
(10-14wUks) weeks
TRAINING DE - TRAINING

FIG. 21. Time courses for changes in 2 mitochondrial enzymes and VO,max during physical condi-
tioning and deconditioning. "Significant changes in time (paired t test) for the selected variables.
[Adapted from Henriksson and Reitman (338).]
594 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

.,. cycle or the electron-transport chain as a function of


the type or intensity of the exercise regimen. With
50
intense interval training, which is as effective in pro-
ducing increases in V0 2 max as continuous exercise, FFA
utilization may be less and thereby fail to elicit any
adaptive response in the enzymes of the ,8-oxidation
ita pathway. An indication of this possibility is found in
a study of eight long-distance runners all having


C)
z V0 2 max above 70 ml.kg-I.min-
I (398). Those who
z trained with continuous exercise possessed higher
:30 HAD activities in the leg muscles than those who
~
trained with intermittent exercise, despite the fact
that SDH activities were identical. Additional support
~
III
0
Q. for this possibility comes from sprint-training studies
I
where CS, SDH, and CYTOX were elevated but HAD
W
a: 20 was unchanged (104). In concert with this are the
Q.
results from a study of sedentary subjects and individ-
:I:
0 uals involved in a variety of sport activities (43). Those
III persons who participated in game-type activities had
10 lower HADjCS ratios than the sedentary or endur-
ance-trained individuals.
Histochemical staining for NADH-nitrotetrazolium
reductase or SDH clearly demonstrates that the ele-
vation of oxidative enzymes can occur in all fiber
types. Morphometric studies have demonstrated that
PRE- SOH = 3.9t.1 3.8t.34.0t.3 mitochondrial volumes increase in FT b and FTc as
(n=8) (n=10) (n=8) well as ST fibers with physical conditioning (9, 104).
These findings are consistent with quantitative bio-
FIG. 22. Mean change in percent of succinate dehydrogenase
(SDH) activity of vastus lateralis with different training procedures. chemical assessments of the SDH activity of ST and
Note that the mean values SD for the absolute activities are FT fibers after interval and continuous training that
similar before the training started. N, no training; S, sprint; E, elicited elevations in both the total body V" 02max and
endurance trained; *, significant difference, P < 0.05. [Adapted from the SDH activity of mixed-fiber muscle preparation of
Saltin, Gollnick, et al. (603).]
the two groups (337, 338). The largest increases in
SDH activities of pooled samples of the ST and FT
smaller amounts of surface protein needed to support fibers occurred after continuous or interval training,
the cristae. Other studies (142,422,423) do not support respectively. Cross-sectional studies have demon-
this contention. strated that SDH activities of FTa and FT b fibers can
For human skeletal muscle almost all existing data reach values as high as those of ST fibers with exten-
support the concept of a constant proportionality of sive training (398). In such instances the SDH activi-
enzymes. Thus increases in SDH and CYTOX activi- ties of FTa and FT b fibers were 4-fold higher than
ties occur in concert (322,338). Thus the capacities of those of sedentary subjects, whereas the activity of
the citric acid cycle and the electron-transport chain the ST fibers was only 2.5-fold above that in the
change in parallel. Whether enzymes in the ,8-oxida- sedentary individuals (Table 10).
tion pathway adapt in similar proportion is unknown.
In one of the few studies where marker enzymes for TABLE 10. Succinate Dehydrogenase Activity of
all of the major mitochondrial pathways were fol- Thigh Muscle Fiber Types in Response to
lowed, CS and CYTOX increased similarly though Conditioning and Deconditioning
with a slightly different time course, but HAD was
unchanged (104). In fact a small decline was noted Range for Muscle Fiber Types
Maximal Mixed
after 6 mo of training. These data are in contrast to Condition
Oxygen Muscle
ST FT.
those from a study with middle-aged men where a Uptake
similar type of training (jogging, playing basketball, ml.kg I.min I urnol-g-rnin I

etc.) produced parallel increases in SDH, CS, and Deconditioning 30-40 5.0 4.0 3.5 4.0
HAD activities (43). The activity of HAD was ob- Sedentary 40-50 9.2 5.8 4.9 7.0
served to be present in a constant proportion to either Conditioning 45-55 12.1 10.2 5.5 11.0
(months)
SDH, CS, or CYTOX in cross-sectional studies of Endurance >70 23.2 22.1 22.0 22.5
endurance-trained subjects with the ratio being close athletes
to 1.0 (0.8-1.4) (364, 398). It is, however, conceivable ST, slow twitch. FT., FT h , fast-twitch fibers of the thigh muscles.
that training could produce differential responses in Approximate values for maximal oxygen uptake are included.
enzymes of ,8-oxidation as compared to the citric acid (Adapted from data in refs. 299, 337, 398, 602.)
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 595

Immobilization or inactivity causes SDH activity to physical activity was the report of 50%-100% increases
fall. This is true for sedentary and well-trained sub- in SDH activity in the hindlimb muscles of the rabbit
jects. In sedentary subjects the largest reductions oc- after 20-30 min/day of direct electrical stimulation for
cur in the ST fibers such that the difference in SDH 15 days (113). Subsequent studies where rats were
activity of the various fiber types in deconditioned exercised with programs of swimming did not confirm
muscle is small (299). This is somewhat in contrast to the existence of high activities for SDH or malic
the findings for the glycolytic enzymes and indicates dehydrogenase (283, 317, 353).
that physical activity regulates the level of the mito- The application of methods where rats were forced
chondrial more than the glycolytic enzymes. to run either on treadmills or in exercise wheels for
An important aspect of the detraining studies is that prolonged periods oftime (up to 2 h) at speeds between
rate constants for the turnover of the enzymes can be 27 and 32 m/rnin firmly established the fact that
estimated from them. Thus it has been estimated that endurance training increases the capacity of the citric
the half-life of cytochrome oxidase is about 8 days in acid cycle, fat oxidation, and the electron-transport
rat skeletal muscle (62, 677). Data on this subject for system (26,46,62, 142,328,345,353,354,357,434,495,
man are incomplete, and an exact evaluation of the 678,723,732). When the exercise is sufficiently intense,
regulation of enzyme levels is currently not available. the increases in mitochondrial enzymes occur some-
A single exercise bout has been shown to produce an what in parallel in all fiber types present in the muscles
increase in the synthesis of components of cytochrome (678). The effect is a result of an increase in mitochon-
c (358). Some evidence suggests that the turnover dria (39, 266, 268, 353, 422, 505). Histochemical stain-
rates are similar for the muscle of man and rat. In ing of muscles from sedentary and trained animals for
studies with man, comparisons can also be made be- oxidative enzymes results in an increased staining
tween the rate of change in V0 2max and the aerobic intensity. As the staining intensity of the fibers that
capacity of the limb muscles (Fig. 21). From such are normally low in mitochondrial enzymes (FT fibers)
studies it is apparent that the enzyme activities decline increases, it becomes increasingly difficult to discrim-
faster than the V02max (7,425), the former approaching inate between these and the normally oxidative fibers
pretraining values in 2-3 wk. At this time V0 2max was (ST). This has lead some investigators to conclude
still 10% higher than the pretraining value. that endurance training produces a conversion of one
Lipoprotein lipase is an enzyme located on the in- fiber type to another (39, 172,213,214,497). But since
traluminal surface of the capillaries, and it has a key the oxidative capacity of all fiber types increases with
position in the utilization of plasma triglycerides by the relative ratio between fiber types remaining rather
the tissues. The enzyme is synthesized by skeletal constant, this does not constitute a change in the basic
muscle cells and found in skeletal muscle of man (459, phenotype of the fibers.
460). Lipoprotein lipase activity is related to the degree Since all components of the oxidative system appear
of capillarization of the skeletal muscle (461), and it to respond in parallel to endurance training, the result
could therefore be expected that it would become is that the skeletal muscles of endurance-trained ani-
elevated when capillary density is increased with phys- mals possess greater capacities for the oxidation of
ical training. No studies are yet available on this pyruvate, fatty acid, and ketone bodies. Although the
subject in man. It is demonstrated, however, that majority of the work in describing the adaptive re-
prolonged exercise causes an acute pronounced en- sponse of skeletal muscle to endurance training has
hancement of the lipoprotein lipase activity (462). used the rat as an experimental subject, similar re-
Variations due to the previous 24-h physical activity sponses have been reported for the guinea pig, bush-
level may mask any changes due to a more permanent baby, and horse (36,39,169,646,692). Similar changes
elevation of the physical activity level. On the other have also been observed in the rat diaphragm when
hand it could be anticipated that along with more airway resistance was increased by an experimentally
capillaries there would be more binding sites for the imposed stenosis of the trachea (420). It should also
lipoprotein enzyme, and this would provide an expla- be noted that the metabolic potential of the neuro-
nation for higher lipoprotein lipase activity after pro- muscular junction also adapts to endurance training
longed exercise in the trained stage. (138).
The effect of physical activity on the oxidative ca- Short, high-intensity exercise such as sprinting pro-
pacity of skeletal muscles of animals has been exten- duces smaller augmentations of the oxidative path-
sively and intensively investigated. The models used ways (608). Thus 11 wk of training rats with a sprint
for increasing activity have included electrical stimu- program of alternate periods of 30 s of running and 30
lation (either direct or via the motor nerve), varying s of rest with the final running speed being 80 m/rnin
durations of swimming, endurance running, sprint run- did not alter SDH activity in any of the fiber types
ning, and isometric contractions. Inactivity has been (608). A sprint program with fewer repetitions has
imposed on the muscles by denervation and by limb been reported to increase the CS and hexokinase
immobilization either by the application of restrictive activities in the rectus femoris and soleus muscles of
casts or joint immobilization. the rat (659). Creatine kinase was unchanged in the
One of the earliest indications of an adaptive re- rectus femoris and increased in the soleus muscle in
sponse of the oxidative systems of skeletal muscle to this experiment. Similarly 16 wk of sprint training was
596 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

reported to increase the fumarase activity for the in this chapter, skeletal muscle fibers are classified
soleus, the white portion of the gastrocnemius, and only on the basis of their contractile properties as can
the plantaris muscles of the rat (345). A training be identified from histochemical, immunological, elec-
program of isometric contractions had no effect on the trophoretic, or biochemical characterization of myofi-
oxidative potential of rat skeletal muscle (208). brillar proteins. Thus a true interconversion of a fiber
Chronic electrical stimulation of skeletal muscle via is characterized by changes in contractile properties
the motor nerve produces an overall increase in the and in the manner that a fiber is utilized during
activity of the oxidative enzymes (323, 371). exercise,
Inactivity by various experimental procedures There is no question that under appropriate condi-
causes a precipitous fall in the oxidative capacity of tions muscle fibers are mutable. Perhaps the first of
skeletal muscle (316, 350, 670, 671). This has been these situations occurs during maturation after birth.
reported to be about 70% for succinate-cytochrome c At birth many of the skeletal muscles of the limbs of
reductase, and about 50% for CYTOX of the rat gas- mammals possess contractile properties similar to the
trocnemius in 21 days. Malate dehydrogenase was 40% ST muscle ofthe adult (92). During the early postnatal
and 70% lower in the gastrocnemius and soleus mus- period some of these muscles undergo changes in their
cles, respectively, of the rat after denervation. The biochemical composition such that their speed of con-
overall picture for inactivity produced by de nervation traction attains that of the adult FT muscle (157).
is for a major reduction in the oxidative capacity of all During this process the myosin in fetal muscle, which
types of skeletal muscle. is initially undifferentiated, takes on the characteris-
Immobilization of limbs has also been reported to tics associated with the myosin of mature FT muscle
result in decreases in the oxidative capacity of animal (157, 718). The relative speed with which this conver-
muscle (60,64,439,474,479,582). This effect, however, sion occurs is a function of the initial size of the
is less dramatic than that occurring with denervation newborn and the rate at which a given species matures
and may be minimal when the enzyme activities are (92,93,119,122). For example, for the rat the extensor
expressed per unit of muscle (170). There are, however, digitorum longus attains a contractile speed similar to
reports of changes in the mitochondria with reduced that of the mature animal by 21 days of age (157).
capacities to oxidize glucose, pyruvate, palmitate, and During this period the ATPase of actomyosin in-
,B-hydroxybutyrate (583). The changes are more rapid creases in parallel with the time to peak tension.
in ST than FT muscle (64). These data suggest that Conversely the one-half relaxation time changes in
qualitative and quantitative changes had occurred in concert with the development of the Ca 2+ -sequestering
the mitochondria with immobilization. capacity of the sarcoplasmic reticulum (157).
Studies conducted with man closely parallel those It is also a consistent observation that the reinner-
with animals for changes in the mitochondrial en- vation of a denervated muscle with a motoneuron that
zymes. This includes the methods for tissue analysis normally innervates a muscle with dissimilar contrac-
and many procedures for producing increases and tile properties (i.e., an ST muscle with a nerve nor-
decreases of physical activity. Interestingly most of mally innervating an FT muscle or vice versa) results
the enzyme assays were first developed with animal in the muscle taking on the contractile and biochemi-
models and then applied to man. Overall the responses cal properties associated with the new nerve (33, 121,
observed in skeletal muscle to altered physical activity 122,151,351,421). The experimental basis ofthis cross
are similar for animals and man. In each group of innervation came from the observation of Eccles and
subjects there are certain advantages and disadvan- co-workers (165-167) that the contractile properties of
tages for their use. It has been possible to use some a muscle were associated with the characteristic pat-
experimental perturbations with animals that are not tern of the neural impulses delivered to the muscle.
possible with man, for example, the experiments with For the adult cat, ST muscle is innervated by moto-
chronic electrical stimulation of the muscle via the neurons that discharge tonically at low frequencies,
motor nerve. There is some activity in the area of whereas FT muscles receive chronic impulses in a
direct electrical stimulation of muscle of man via the phasic manner at higher rates (167). These data sug-
nerves at motor points. Such studies may apply to gested that the stimulation frequency of the nerve or
rehabilitation medicine and also to athletes during the release of some neurotrophic substance associated
periods of injury. Conversely there are advantages in with the pattern of nervous discharge was responsible
the study of man. Foremost among these is the ability for determining the contractile properties of the mus-
to use specific experimental protocols that require the cle or of the individual motor units. The cross-inner-
cooperation of the subjects, such as the one-leg model, vation studies support such a contention. Chronic
and a wide variety of individuals are available who electrical stimulation produced by electrodes im-
naturally engage in physical activity or who are sed- planted on the motor nerves and applying stimulation
entary. frequencies mimicking those of the opposite nerve
Contractile properties and fiber conversion. One produces a similar conversion of the contractile and
important question concerning the adaptability of chemical properties of the muscles (323-325, 371, 551-
skeletal muscle to varying types of overload is whether 553, 568, 599, 600). These data conclusively demon-
there is a change in the fiber types. As stated initially strated that all muscle cells retain a "genetic memory"
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 597

for the synthesis of all kinds of proteins associated whether or not the fiber distribution of skeletal muscle
with the regulation of the contractile properties. can be altered by an interconversion of one type to
Whether the conversion of a muscle from an ST to the other as a result of some form of "normal" physical
an FT or the reverse depends exclusively on the fre- activity. The logical conversion would be for an in-
quency of the stimulation or on a neurotrophic sub- crease in the ST fibers in response to endurance type
stance released from the nerve independently of the activity and the appearance of a greater percentage of
impulse frequency has been questioned. Two experi- FT fibers for those activities where short' explosive
mental approaches have been taken to this problem. contractions are required. In most of the early studies
In the first study the soleus muscle of the rat was with animal species other than man the fibers were
denervated and electrodes implanted in it. Low-fre- identified simply as red or white on the basis of stain-
quency impulses delivered at a mean of either 1 or 9 ing intensities for oxidative enzymes. With such meth-
Hz did not alter the time to peak tension but at a ods it was reported by a number of investigators that
mean of 9 Hz the one-half relaxation time was pro- there was a higher percentage of red than white fibers
longed (465,488). Both the time to peak tension and in the muscles of endurance-trained animals (39, 172,
one-half relaxation times were reduced when the stim- 213, 214). Termination of the training program re-
ulation was 100 Hz for 0.01 or 1 s. At a mean stimula- sulted in a return to the control situation. By some
tion rate of 1 Hz, endurance was reduced. Reinnerva- this has been interpreted as a conversion of white to
tion of the denervated muscle by nerves normally red fibers. A similar report also exists in a longitudinal
innervating ST muscle resulted in the appearance of study of the effect of training on human skeletal
the ST contractile characteristics in spite of a contin- muscle (497). Such an alteration in the staining inten-
ued direct electrical stimulation (469). These data sity for mitochondrial enzymes is consistent with bio-
demonstrate that although direct stimulation can have chemical studies demonstrating that endurance train-
a regulatory role in the contractile properties of mus- ing induces increases in mitochondrial protein concen-
cle, ultimately the motor nerve is dominant. These trations and in the activities of the oxidative enzymes
data do not, however, answer the question of whether associated with the mitochondria. As seen in Table 10
this neural dominance is due to the natural impulse this increase in oxidative potential of the muscle can
traffic mediated by acetylcholine or to neurotrophic occur in all types of fibers if the intensity and duration
substances. Chordotomy, which produces electrical are adequate to produce recruitment of all motor units
silence of the nerves, may give some insight into this in the muscle. On the other hand the short, heavy-
question. When the spinal cord is sectioned, there is a resistance exercise of weight lifting results in a de-
conversion of ST to FT muscles (187). This change is crease in the oxidative potential of skeletal muscle.
rather slow and occurs in concert with a shift of the This could be viewed as an increase in the white fibers.
myosin isozymes to those of the FT muscle. When The criterion that has been established to identify
considered in light of the results from electrical stim- fiber type is a difference in the myofibrillar proteins.
ulation applied directly to denervated muscle, these On this basis changes in oxidative potential do not
data suggest that the prime determinant of the con- represent a change in fiber type.
tractile properties of muscle fibers is the electrical A significant amount of data are available on the
activity rather than a neurotrophic factor. These stud- fiber composition of muscles of athletes. The majority
ies do not rule out the existence of neurotrophic reg- of these data have come from studies that determined
ulators, only that without normal electrical traffic over the fiber composition in biopsy samples. As a result,
the end-plate region they are not effective, or that there is appreciable descriptive information on the
electrical traffic in the nerve is required for a normal fiber distribution of several muscles from athletes
transport of these substances from the nerve or across specializing in a variety of athletic events (see Table
the motor end plate. The observation that there is a 8). In most of these studies the fiber composition has
conversion of ST to FT fibers after chordotomy sug- been assessed from the histochemical identification of
gests that the maintenance of ST properties depends fibers on the basis of the histochemical demonstration
on chronic electrical activity. of myofibrillar ATPase. In some instances this has
Experimental chordotomy is like spinal cord section been combined with procedures that illustrate the
in man resulting from accidents. In such patients all metabolic profiles of the fibers from histochemical
fibers in the paralyzed muscle stain histochemically as staining procedures. From cross sections the fiber com-
FT fibers (292). Also, in hemiplegic patients there is position of athletes has been found to fall within the
an increase in percentage of FT fibers in the muscles range for normal subjects (602). Since the range en-
of the affected side (444). These data illustrate the compassed by normal subjects is rather large, this is
mutability of human skeletal muscle. This is consistent not surprising.
with the conversion of ST to FT fibers in the muscles In spite of the fact that most athletic subgroups
where the nerve is intact but electrically silent. These have fiber distributions in their muscles that are
data suggest that for the maintenance of slow-twitch within the range of normal subjects, there are some
properties the nerve must be chronically active. indications of selective fiber distributions in certain
Although interesting and important the above ex- athletic groups. Most notably, individuals who excel
perimental approaches do not answer the question of in events requiring great endurance usually possess a
598 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

predominance of ST fibers in their muscles. Con- and FTb fiber. This was in part compensated for by a
versely there is a tendency for a person with sprint 5% increase in the FTc fiber population. Six months
abilities to have slightly higher percentages of FT after termination of the training there were no differ-
fibers. In the latter case, however, the situation is less ences in fiber distribution as compared to that at the
dramatic than for endurance athletes. On this basis it end of the training period.
has been tempting for some to speculate that pro- Pette et al. (545) have observed a similar pattern of
longed exposure to a given type of muscular activity myofibrillar proteins when comparing FTa and FT b
can induce a conversion of one fiber type to another. fibers. There is also a lack of definitive proof that
There are, however, few longitudinal studies to sub- normal physical activity produces a change from a
stantiate this supposition. Gollnick, Saltin, and co- fast- to a slow-type fiber or the reverse in animals.
workers (260) examined the fiber composition of bi- Bagby, Gollnick, et al. (22) did not observe any change
opsy samples from the vastus lateralis muscle of six in the percent distribution of the fibers of the gastroc-
subjects before and after a 6-mo training program nemius muscle after either an endurance- or sprint-
consisting of bicycle exercise. Since this type of exer- training program. Chronic overload, however, pro-
cise depends to a large extent on the quadriceps muscle duced by inactivation or ablation of a synergistic mus-
group, this muscle should have undergone extensive cle or by chronic stretch produces an increase in the
use. The oxidative potential of the muscle was doubled percentage of ST fibers in rat (296, 379) and chicken
at the completion of the training period, which sup- (359) skeletal muscle. Thus the potential for an inter-
ports this contention. The fiber composition, as deter- conversion of fibers does exist when the stimulus is
mined by staining procedures to identify fibers only as appropriate.
FT or ST, was not altered by the training. Since the In summary, it appears that training does not pro-
FT fibers were not further differentiated into the FTa, duce any major shifts in the population of ST and FT
FT b , and FTc, there was no indication of shifts in the fibers in skeletal muscle. Unfortunately there is cur-
distribution within this fiber group. However, if a rently a lack of longitudinal studies that have encom-
major shift in the fibers in the two major types did passed a large enough sample and included all of the
occur, it should have been detectable with the methods techniques that can be used to identify fiber-type
that were used. Jansson et al. (399) have examined the interconversion to settle this issue. The current data
fiber composition in samples from the vastus lateralis suggest that it may be possible to induce some shifts
muscles of four subjects after 18 wk of endurance in distribution of the subgroups of the FT fibers.
training and again after an additional 11 wk oftraining Mechanical properties. There are few reports that
that included exercise at high relative oxygen con- examined the contractile properties of enlarged skel-
sumption. During the period of endurance training the etal muscle. Some of the early experiments in this field
subjects ran an average of 110 km/wk. The second produced a muscular enlargement by elimination of
training program included some high-intensity exer- the synergistic muscle via tenotomy. With this model
cise (at 90%-100% of the V02 m a x ) in conjunction with a slowing of the normally ST soleus muscle was ob-
endurance running. The average distance run per week served in both the cat (709) and rat (451). There was
was 71 km. Since samples were not taken before ini- also a decrement in the maximal tetanic tension per
tiation of training, no comparisons could be made square centimeter 6 days after the onset of the over-
between the sedentary and endurance-trained state. load. There was no change in the contractile properties
After the second training period there was a 17% of the FT plantaris muscle of the rat after enlargement
reduction in ST fibers. This was accomodated by an produced by denervation of the soleus and gastrocne-
increase in the FTc (type IIC) fibers. The suggestion mius muscles or by the combination of denervation of
was made from these data that a major conversion of the synergistic muscle and treadmill exercise (56, 57).
fiber types could occur as a result of training. These In the latter experiments the time span between im-
authors also referred to data where the percent of ST position of the overload and assessment of the con-
fibers decreased from 81% to 57% in the muscle of a tractile properties of the enlarged muscles was 10 wk.
well-trained cross-country skier after a 6-wk period of The muscular enlargement averaged about 35% and
limb immobilization due to an injury. This conversion was similar whether the rats were exercised or not.
of the ST fibers to a class of FT fibers as a result of The major differences between these experiments
high-intensity exercise is not in agreement with the were the choice of mus-cle studied (an ST vs. an FT
data of Saltin, Gollnick, et al. (603) comparing the muscle) and the time span between the imposition of
fiber composition of legs of subjects studied in com- the overload and assessment of the contractile prop-
binations of no training, endurance-training, and erties. The latter difference may be significant since it
sprint-training practices with one leg. Henriksson et has been demonstrated that there is a major increase
al. (335) examined the effect of a 50-day program of in the water content of the overloaded muscle after
endurance training (skiing 18 mi/day) on the fiber tenotomy or ablation of the synergistic muscles (378).
composition of the human triceps brachii muscle. Thus even if the contractile properties are corrected
There was no difference in the percent of ST fibers for such differences and expressed on a dry weight
before and after the training. However, there was a basis, this does not preclude the possibility that in the
reduction of about 11% in the total population of FTa intact cell normal contractile activity was disrupted as
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 599

a result of the superhydrated state. After 4 wk this and frequency of the exercise stimulus. This suggests
situation no longer exists, and the protein content and that specific stimuli are generated by different pat-
activities of the glycolytic and oxidative pathways are terns of use and that these are somehow sensed and
normal (18, 378). translated into adaptations in the muscle. Presently
Only a few reports are available that examined the very little is known concerning the nature of the
contractile properties of skeletal muscle fibers after stimuli or the manner in which they are translated
physical training. A program of sprint training was into a genetic expression.
reported to shorten the time to peak tension of the rat The increased tension associated with high-inten-
soleus muscle by 14% (659). However, this program sity muscular contractions may be responsible for
did not alter the contractile properties of the FT rectus increases in muscle mass. Such increases in muscle
femoris muscle. This could be interpreted as a specific size can be demonstrated with chronic stretch of either
change to enhance running speed. In cats a weight- normal or denervated muscle (206, 427, 648). This
lifting program that lasted from 10 to 61 wk was stretching of muscle can also prevent the atrophy
reported to increase the time to peak tension for the associated with limb immobilization (64). The unan-
flexor carpi radialis and palmaris longus muscles (both swered question is how stretch stimulus is communi-
normally FT muscles) (277, 278). In neither of the cated as a specific chemical signal to the genes to
aforementioned experiments were measurements induce the synthesis of proteins specific for muscular
made of the ATPase activity of myosin. In the latter enlargement. A commonly suggested chemical mes-
experiments there was no evidence of a change in fiber senger is the level of free calcium (206). The idea is
type as demonstrated from the histochemical staining attractive, but it has not been demonstrated that the
for myofibrillar ATPase. In contrast to these obser- elevation of free calcium associated with muscular
vations, Buchthal and Schmalbruch (89, 90) did not contractions induces adaptations in these systems.
observe any differences in the contractile properties of Furthermore it is difficult to imagine this applying to
the biceps brachii and triceps muscle of weight lifters. growth and development as influenced by physical
Endurance training did not alter the contractile prop- activity or to weight-lifting activities as practiced by
erties of the plantaris muscle of the Galago senega- humans. In the latter instances the actual time of the
lensis [lesser bushbaby; (169)] or of the gastrocne- physical activity when the muscle experiences high
mius-plantaris muscle group of the guinea pig (37). An tensions may be extremely brief. Under these condi-
exception to this general pattern of a lack of a major tions it would be expected that the level of free calcium
change in the contractile characteristics of muscle would return to normal as it would after all types of
after training is the report of a 14% decrease in the motor activity. Direct electrical stimulation of skeletal
time to peak tension of the rat soleus after treadmill muscle cell has also been reported to increase the
exercise (223). An increase in myofibrillar ATPase synthesis of myosin (70).
activity has also been reported after endurance train- It has been suggested that the level of free creatine
ing (28), and a decrease with overload produced by could induce protein synthesis, based on early experi-
surgical ablation of a synergistic muscle (67). The ments measuring the rate of actin and myosin synthe-
latter change is consistent with the greater percentage sis in muscle cultures from the chicken embryo (388,
of ST fibers as identified by the histochemical method 389). More rigorous tests of this possibility have failed
in the enlarged plantaris after ablation of the gastroc- to reproduce the initial observation (236). Since CP is
nemius muscle (378). reduced in the muscle during submaximal and heavy
Forced inactivity such as occurs after immobiliza- exercise, the release of free creatine should occur under
tion of a limb has been studied from the standpoint of both conditions. But since there is no increase in total
its effect on the contractile properties of skeletal mus- muscle bulk with the submaximal exercise, it seems
cle. Immobilization of the hindlimb of the Galago unlikely that creatine could be a major factor control-
senegalensis for 5 to 6 mo did not alter the contractil- ling the synthesis of myofibrillar protein. Another
ity of the FT plantaris muscle (170). In contrast an possibility would be that an intracellular elevation
elongation in the contraction times for both the ST either of specific or general amino acids induces pro-
and FT muscles of the cat hindlimb was noted after tein synthesis. This hypothesis is related to the fact
22 wk of immobilization (127). that after exercise there is an increased entrance of
The general consensus from the literature appears amino acids into the muscle cell (245-247). Animal
to be that there are no major changes in the contractile studies have also indicated that overloads produce
characteristics in response to varying types of physical increases in ribonucleic acid (RNA) and RNA poly-
training or inactivity. In cases where changes have merase in skeletal muscle (307,586,647). Similar meas-
been reported there is a lack of an unequivocal dem- urements on denervated muscle also support this no-
onstration that there has been a change in the basic tion (426).
type of fibers of the muscles. The situation regarding the control mechanism for
the increases in energy-releasing enzymes is equally
REGULATION. Clearly the adaptive response of sub- unclear. Several hypotheses have been proposed. Be-
strate levels and enzyme activities that occurs in skel- cause the activities of the enzymes for end-terminal
etal muscle varies as a function of the type, duration, oxidation respond most dramatically to prolonged ac-
600 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

tivity, it has been suggested that this is a response to Stimulation of the f3-receptors of the skeletal muscle
hypoxia. This assumes that the total muscle or parts has also been suggested as a mechanism for inducing
of the muscle become hypoxic during exercise. This alterations with training (313, 314). When this hypoth-
may be false. Low oxygen tension has been measured esis was tested in rats through a chronic f3-blockade
in skeletal muscle at rest when the number of perfused and sympathectomy, CS, CYTOX, and SDH increased
capillaries is lower than during activity (361, 362, 648). equally in the treated and untreated animals with
In fact with exercise the variation in intracellular endurance training (339).
muscle fiber oxygen tension is reduced and fibers with In the vast number of experiments varying the
very low values are not observed at higher exercise electrical stimulation pattern to a muscle, distinct
rates than in resting muscle (361, 362). Moreover adaptations are obtained related to the type of stim-
hypoxia during exercise could be assumed to be accom- ulation. Tonic, slow-impulse traffic generates an en-
panied by elevations in the lactate concentration of hancement of the oxidative enzymes, whereas high-
both muscle and blood. Mitochondrial enzymes in- frequency, phasic stimulation does not (465). The
crease in muscle in response to training regimens adaptations occur whether the stimulation is via the
where no appreciable elevation in lactate occurs in nerve or directly to the denervated muscle (465). This
either blood or muscle. Some support for the lack-of- suggests that it is the pattern of muscular usage pro-
oxygen hypothesis as a stimulus for inducing increases duced by the electrical activity that is the controlling
in oxidative enzymes comes from studies on patients factor.
with intermittent claudication and on high-altitude The findings described above lead to the general
natives (9, 42, 105, 140, 580). Mitochondrial enzyme conclusion that the stimulus for adaptive changes in
levels, as well as mitochondrial volumes, have been the muscle fiber is related directly to the actual use of
reported to be higher in the most severely affected leg the fiber. This suggests that the inducers of these
of such patients (9, 105). These values were higher modifications are local in nature and depend on the
than those of control subjects. However, examination internal conditions within the muscle fibers. Since
of the rare patients with unilateral stenosis of the similar adaptations can be induced by continuous or
arteries to the leg has failed to verify the existence of interval exercise, there are obviously many methods
a different level of SDH or CYTOX activities between for inducing these local changes. Presently there is no
the normal and the affected leg (336). indication as to the nature of the inducer for the
The notion that high-altitude residents have higher synthesis-specific proteins or how it is related to phys-
oxidative enzyme activities in their muscles is based ical activity. The adaptations preclude the existence
on measurements from permanent residents of the of a general inducing factor such as a change in the
Andes (580). When these measurements were repeated level of an unknown factor in the blood.
and the work capacity of the subjects taken into A number of reports have appeared in which elimi-
account, it was found that men native to an altitude of nation of the major hormones known to be regulators
3,700 m had oxidative enzyme levels similar to sea- of protein synthesis and body growth has not blocked
level residents with comparable patterns of physical the adaptation in mitochondrial enzymes to chronic
activity (604). Conversely sea-level natives who so- exercise (266, 680, 694) or in muscle mass in response
journ at high altitude do not have an increase in the to acute overloads (52, 244, 693). Furthermore in-
activities of oxidative enzymes in the skeletal muscles creases in RNA, amino acid uptake, and protein syn-
(Fig. 23). In fact if anything, there is a slight decrease. thesis occur in the isolated, overloaded heart (618-
The latter finding may be due to a reduction in activity 622) where there is no hormonal control. Thus non-
associated with living at high altitude. Thus the hormonal factors must be given close examination. It
strength of the arguments for tissue hypoxia as the is known that synthesis of enzymes can be induced by
major stimulus for the adaptive response of the oxi- elevation in substrate concentrations (221). There are
dative enzymes of the mitochondria appears to be a number of substrates that become elevated during
limited. The observation that the greatest increases in exercise including citrate, lactate, malate, and glucose
the oxidative enzymes occur with endurance-type 6-P0 4 (198, 200, 269). None of these has been demon-
training, as compared to sprint and weight-lifting ac- strated to be an inducer for the synthesis of compo-
tivities during which hypoxia would be greatest, is also nents of the metabolic pathways. The fact that all
indirect evidence against tissue hypoxia as the specific components of the oxidative system increase in con-
inducer of protein synthesis. Moreover it would appear cert appears to suggest that the general flux of sub-
that the FT b fibers of man and the FG fibers of animals strates through the system may be the inducer. Fitch
would function most often under conditions of low and Chaikoff (221) suggested the involvement of a
oxygen tension either because they have a poor capil- concept of "throughput" since the enzyme content of
lary supply or because they are recruited during pe- tissue appears to be directly related to the amount of
riods of high-intensity exercise. If hypoxia were a substrate conversion occurring in a given tissue. With
stimulus for inducing the synthesis of oxidative en- the elevated metabolic rates associated with exercise,
zymes, these fibers could be expected to show very and the total substrate conversion during prolonged
high activities, which they clearly do not. endurance-type exercise, it is entirely possible that a
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 601

mmol Ci t r a t e synthase HAD mmol


kg" min g"min
d.w.
d.w.

FIG. 23. Mean values for 2 mitochondrial en-


zymes [citrate synthase and 3-hydroxyacyl-CoA
60 60 dehydrogenase (HAD)] determined from muscle
samples from vastus lateralis in 9 sea-level resi-
dents at sea level and after an average 32-wk stay
(6-52 wk) at elevation 3,700 m and 16 men born
50 50 and permanently living at this altitude. Note that
high-altitude residents are divided into 2 groups,
those who were physically inactive (job and leisure
time) and those who were active. Maximal oxygen

40
40
uptake (ml . kg-I. min-I) for the sea-level resi-
dents was 39 ml and 36 ml . kg" . min-I at sea
level and high altitude, respectively; inactive high-

mnI
altitude residents had 28 ml and active 46 ml . kg"
. min-I. [Adapted from Saltin et al. (604).]
30 30

Sea level High altitude Sea level High altitude


residents residents residents residents

~ Sea level lIITI Sedent ary

~ Altitude Physical active

substrate flux through the system could be involved ligament strength was below normal 20 wk after re-
in the induction of the increased oxidative capacities sumption of activity after a period of immobilization
of the different fiber types. This may be important from wearing a cast (518).
from the standpoint of the stability of enzymes. En- The differences in ligament strength appear to be a
zymes are known to be more stable in the presence of function of the total amount of ligament present, that
their substrates (128). is, the total cross-sectional area of the ligament. This
In recent years a great deal of information has been is analogous to skeletal muscle in which strength is a
generated concerning the adaptability of skeletal mus- function of the cross-sectional area of the muscle with
cle to a variety of patterns of use and disuse. It would strength per unit area of muscle being rather constant.
appear that there is little need for further experiments Limited data are available that show the effects of
to explore additional types and intensities of exercise training on the connective tissue of skeletal muscle
that can influence some of these well-documented and of differences between the types of skeletal mus-
changes. Therefore more attention should be directed cle. However, it has been demonstrated that with a
toward furthering the understanding of the processes work-induced growth of muscle there is an increased
that induce the specific synthesis of proteins and con- synthesis of both deoxyribonucleic acid (DNA) and
trol the genetic apparatus of the cells involved. RNA in skeletal muscle (225,393) and in the myocar-
dium (491,498). The bulk ofthis DNA has been shown
CONNECTIVE TISSUE to be localized in the connective tissue (225,393,491).
When DNA synthesis was inhibited, chronic overload
The influence of altered states of physical activity still produced an increase in the cross-sectional area
on the strength of ligaments, or in most cases the force of the muscle fibers but without a concomitant prolif-
required to separate the bone from ligament, has been eration of the interfiber support structures (225). Sim-
studied in a number of species including the rat, dog, ilarly the induction of muscular growth in the rat
rabbit, and primate (518,691,692,706-708). The gen- plantaris muscle by sectioning of the tendon to the
eral conclusion from these investigations is that the gastrocnemius muscle has been reported to increase
fluctuations in the strength of the bone-ligament junc- the activity of protocollagen proline hydroxylase activ-
tion parallels the state of physical activity. Moreover ity, thereby suggesting an increased synthesis of con-
early mobility promotes a more rapid return of liga- nective tissue (698). Endurance training of mice
ment strength after surgical repair. It has also been (treadmill running) has also been reported to stimulate
shown that normal ligament strength did not exist 12 connective tissue synthesis in the skeletal muscle and
wk after surgical repair when 6 wk was immobilization tendons of mice (666) and to increase the activities of
and 6 wk was exercise training (691). In primates some of the enzyme for energy metabolism (322). The
602 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

effects of an endurance-training program on the con- Methodology


nective tissue of the rat has produced less conclusive
There are basically three methods that have been
data. Overall this resulted in little or no change in the
used to visualize capillaries in skeletal muscle: 1) in-
total collagen or the chemical composition of the col-
jection of a dye into the capillary lumen, 2) staining
lagen (433). The training was rather short, however,
the capillary wall, and 3) vital microscopy. There are
and did not induce the usual increase in activity of
problems associated with all three methods. Spalten-
mitochondrial enzymes. Interestingly, a greater colla-
holz (650) pioneered this work with injection of a dye
gen content was reported in ST as compared to FT
into the vascular tree. This method can give good
muscle for the chicken and rat (433,446). There was
estimates both of number and length of capillaries. In
an increase in the concentration of collagen in muscle
addition the anatomy, i.e., the structural relationship
of chicken during stretch-induced hypertrophy (446).
between capillaries and muscle fibers, is seen. The
Only limited data are available that concern the effect
drawbacks are that not all capillaries may be filled
of training on the connective tissue of human skeletal
muscle. In one study (665) it was reported that an 8- and that in the preparation for microscopy a profound
shrinkage occurs. The latter problem can in part be
wk training program increased the activity of propyl
accounted for by determination of a shrinkage factor,
hydroxylase in the vastus lateralis muscle of 69-yr-old
but it does not account for possible distortion in the
female but not male subjects. In a population of men
preparative work. Various techniques have been used
ranging in age from 33 to 70 yr Suominen and Heik-
to overcome the nonhomogeneous filling, but at the
kinen (664) observed higher activities of propyl hy-
present time this problem appears to be unsolved and
droxylase in the vastus lateralis muscle of those who
were habitually active as compared to the sedentary an underestimation in the total number of capillaries
can be the result. In preparing the tissue to identify
individuals. Clearly this is an area where additional
the muscle cells, a hematoxylin-eosin stain has been
data are needed.
used. In doing so the nuclei of the cell are stained
quite dark. It is possible that some of the peripherally
CAPILLARIES located nuclei have been misinterpreted as capillaries
stained with dye, resulting in an erroneously high
The capillary is the interface between the skeletal capillary count. This could be a likely explanation for
muscle and the vascular supply that makes the ex- the extremely high capillary densities found in some
change of blood-borne materials possible. Many ofthe earlier studies, as first pointed out by Pappenheimer
features of this exchange were described by Krogh (535).
(435, 436) in his now-classic studies. Since these pi- Techniques to stain the capillaries, either the basal
oneering studies there has been considerable effort membrane or the endothelial cells, have not been used
directed towards furthering the understanding of this as extensively as the injection methods. These tech-
system. Since the functioning of skeletal muscle during niques have the advantage that they can be combined
exercise depends to a large extent on the perfusion of with staining of cross sections of the muscle so that
the muscle with blood, attention is focused here on the fibers in the section can be identified with regard
some of the factors that contribute to this process. to contractile and metabolic characteristics. Further,
This includes a description of the number, length, and these stains can be used on sections of frozen samples,
diameter of the capillaries as they are related to and which minimize shrinkage, and the distortion may also
surround the muscle fibers. Although such measures be at an acceptable level. The major drawback is that
do not give any indication of the number of open only the number of capillaries in cross sections can be
capillaries, of blood flow either at rest or during exer- counted. Further, there is a risk that not all capillaries
cise, or of the permeability characteristics for the are stained. Alkaline phosphatase appears to be the
exchange process, all of which are essential in deter- safest stain for capillaries, but myofibrillar ATPase
mining the transport rate for specific substances, they after acid preincubation also functions in many spe-
do give estimates of the upper capacity for blood flow cies. However, neither of these reactions stain capil-
in the muscle. This situation is similar to the use of laries in human skeletal muscle well (5, 6). The reason
maximal activity (Vmax) for enzymes as an indicator of for this is obscure. The PAS reaction stains the basal
the potential substrate flux through a specific meta- membrane of the capillaries in human muscle. If the
bolic pathway. sections are pretreated with amylase, the capillaries
There has been some attention paid to the effect of can easily be identified [Fig. 4; (5)]. The PAS stain or
varying patterns of physical activity on the capillary electron-microscopic technique for identifying capil-
supply to muscles and of the differences in capillary laries in human skeletal muscle gives the same number
supply that may exist among the different types of of capillaries per fiber (520).
muscle fibers. Since the results of such studies may The vital microscopy technique gives detailed infor-
depend on the methodology used, a brief discussion of mation about the number of capillaries and their
some of the problems associated with each method is length and diameter. The flow rate can also be esti-
given. Further, a short description of the present un- mated in the various capillaries. The problem with the
derstanding of capillary architecture is included. technique is that only a few muscles are suitable for
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 603

use. Moreover the surgical procedure and the light to muscle fibers. Two capillaries may join in one small
visualize the structures can offset the normal state. venule or end at an almost right angle in a larger
This is probably not a major problem when counting venule. The capillaries are joined at regular distances
the capillaries but the diameter of the capillary and by anastomoses. The average length of the capillary
the flow may be affected (196, 281, 477, 483, 509). in this muscle is 1,000 /lm with a large variation around
this mean. The average diameter is slightly smaller
Anatomy than the diameter of the red blood cell of the rabbit
(5.7 vs. 5.5 urn) and somewhat wider in the venular
The arrangement of the capillaries in skeletal mus- than the arterial side. In spite of large differences in
cle was the focus of many of the early studies [(477, the size of the muscle fibers, an almost identical num-
570, 650); for further references, see ref. 370]. In sum, ber of capillaries was found around each of three fiber
in white muscle the majority of capillaries run parallel types (3.5 capillaries per fiber) with a mean of one
with the muscle fibers, but there are also capillaries capillary per fiber giving a sharing factor of 3. With
that encircle the fibers. In red muscle the capillaries the same technique other muscles and other species
have a more tortuous arrangement. They also seem to have been studied and the same general arrangements
form parallel loops. In addition several studies point of the vessels have been found although the values for
to definite widening of some capillaries in the venous number and length of the capillaries vary (477, 507,
end where capillaries join the venules (for references, 509).
see ref. 369). Hammersen (306) has presented evidence that the
In more recent studies, Eriksson and Myrhage have very regular pattern for the microvascular tree ob-
worked out some of the details of the configuration of served in these thin muscles studied by vital micros-
the microvascular supply in the thin and flat tenuis- copy may not apply to all muscles. In his own studies
simus muscle of the rabbit [(196); Fig. 24]. In many using an injection technique to visualize the capillaries
essential parts their results confirm the earlier obser- in various rat and rabbit muscles, the arrangement
vations. Running parallel to the muscle and along its was more complex. He found ramification to adjacent
side are the main feeding artery and a vein. From capillary beds to be much more frequent. Further,
these vessels transverse arterioles and venules branch close to the venous end of the capillary the number of
off at angles of 45 0 -90 0 From such a transverse arter- interconnections rose considerably. Several of the cap-
iole and vein there is a mean of 10-15 branches. After illaries unite to form small venous stems. In addition,
a distance of 1-2 mm the smallest arterioles subdivide unramified capillaries were found that ran along the
into capillaries. These run essentially parallel to the external surface of the fiber bundle, sometimes joining

FIG. 24. A: schematic representation of the vascular arrangement in the tenuissimus muscle. CA,
central artery; CV, central vein; TA, transverse arteriole; TV, transverse venule. B: detailed schematic
representation of the vascular architecture of the tenuissimus muscle. Arterial vessels, open; venous
vessels, filled. Sections of different depth are made into the muscle at II, III, and IV. At I a projection
of the pre- and postcapillary vessels is shown. The section at II shows the vessels above, at III at the
same, and IV under the level of the central vessels. C: graphic representation of a small arteriole
(ART) subdividing into capillaries. Capillaries then run parallel to the muscle fibers. [A adapted from
Eriksson and Myrhage (196).]
604 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

a distant capillary bed. Hammersen's conclusion is available for the chicken, where the number of capil-
that the concept for a "terminal vascular unit" does laries per fiber is approximately 0.5 at birth and in-
not fit for skeletal muscle tissues. Basically, Myrhage creases to 1-1.5 in the adult muscle (65).
and Eriksson (507) reached the same conclusion when In growing rats a very close relationship exists be-
extending their studies to cat gastrocnemius muscle tween body weight and muscle fiber size [r = 0.98
and with an injection technique. These more recent (633)]. Thus with enlargement of the body and a
studies have also brought new evidence on controver- smaller metabolic rate per weight of the animal, skel-
sial topics such as arteriovenous anastomoses and etal muscle capillarization also goes down. This is in
capillary sphincters (161, 196, 361, 362, 477). In none line with the old observations [for references, see
of the studies with vital microscopy could the presence Hudlicka (369)] that small animals have a higher
of arteriovenous anastomoses be verified. Besides, the capillary count than larger species. A good illustration
ultralong unramified capillaries described by Ham- of this is found in the work by Schmidt-Neilsen and
mersen did not function as an arteriovenous anasto- Pennycuik (617). They studied the masseter muscle
mosis (306). The explanation offered for regulation of from 10 species varying in weight from 9 g (bat) to
flow in various capillaries is that smooth muscle cells 200-450 kg (pig, cattle). The number of capillaries per
in the wall of the terminal arteriole surround the fiber was surprisingly similar (1-2.5) but the number
capillary at the branching point and function as of muscle fibers per square millimeter was around
"sphincters," because no precapillary sphincters can 2,000 in the bat and 500-1,000 in pigs and cattle,
be detected with a vital microscopy technique. How- resulting in over 3,000 capillaries/rnm" in the bat and
ever, Hammersen has pointed out that these can be fewer than 500 in the pig.
difficult to visualize with this technique (306), and the
existence of capillary sphincters remains to be proved. MUSCLE FIBER TYPES AND POTENTIAL FOR OXIDATIVE
METABOLISM. Ranvier was the first to demonstrate a
Capillary Density difference in red and white muscles in degree of cap-
From the very first studies of skeletal muscle capil- illarization (570). Since then quite a few studies have
presented evidence in support of this early finding, but
laries, the number per fiber or unit area has been
systematic studies on the subject are scarce. The
estimated. Rather complete lists can be found in re-
explanation is that with injection techniques it is
views by Hudlicka (369, 370). The significance of an
difficult to identify fiber types and their metabolic
estimate of the number of capillaries in a muscle is
potential. Romanul (588), combining a stain for alka-
limited as long as length and diameter of the vessel
line phosphatase to visualize capillaries in muscles
are unknown. However, capillary number in a cross
from the rat, rabbit, and man with stains for mito-
section of a muscle fiber bundle can give information
chondrial enzymes, has made a plea for a very
on several subjects of importance for the understand-
close coupling between the oxidative metabolic capac-
ing of skeletal muscle capillary physiology.
ity of a fiber and the number of capillaries surrounding
GROWTH AND DEVELOPMENT. Postnatal growth of the fiber. Further, in studies with cross innervation of
skeletal muscle is due to enlargement in both diameter muscles the capillary count did change in relation to
and length of existing muscle fibers. This means that alteration in the oxidative capacity of the muscle fibers
the capillaries surrounding the fibers are pushed apart, (590). He supports his contention with excellent mi-
and the number of capillaries per square millimeter crographs, but no detailed mathematical treatment of
(density) decreases. The most detailed studies have the results is presented. Ample evidence is available,
been in growing rats, where capillary density and however, demonstrating differences in capillaries of
muscle fiber size in various muscles have been exam- ST and FT fibers (cf. Fig. 4). This appears to be true
ined in rats weighing from 90 to over 600 g. Over this for both human and nonhuman species. In the medial
range of weights, the number of capillaries per square gastrocnemius muscle of the guinea pig and the rabbit,
millimeter was lowered from 1,300 to 400-500 in the the difference is not pronounced (473), but in the
gastrocnemius and soleus muscles (584, 633, 634). A lateral head of the gastrocnemius muscle and tibialis
similar trend was found for the tibialis anterior muscle, anterior muscles of the rabbit, the difference is more
but the absolute values were higher. The number of substantial (633). This is not directly apparent from
capillaries surrounding the fibers increases with en- values of capillaries per square millimeter or per fiber.
larged muscle fiber size, with a concomitant increase The size of the various fiber types also has to be taken
in sharing factor. The reduction in capillary density is into account, as ST fibers usually are smaller than FT
less, however, and the increase in capillaries surround- fibers.
ing the fibers is larger than could be anticipated from Gray and Renkin (285) found in their detailed study
the growth of fiber size. This is due then to an increase of muscles of the rabbit that the average capillary
in capillaries per fiber found with development. In the density was twice as high for ST as for FT fibers. On
aforementioned muscles of the rat the number of this particular topic a considerable amount of infor-
capillaries per fiber increased from 1 to 2 (gastrocne- mation is available on human muscle, as so many of
mius) and 1 to 3 (soleus) (633,634). Similar results are the studies of capillaries in human muscle have utilized
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 605

serial frozen sections where staining of the capillary to the most distant point between capillaries along the
basement membranes was done concurrently with periphery of a fiber in cross section; the point being
evaluation of metabolic profile and muscle fiber type that mitochondrial density is largest underneath the
(5,8,11,313,326,520,523,602). In mixed muscles such sarcolemma with fewer mitochondria found centrally
as the gastrocnemius, the number of capillaries sur- (364,422). What adds to the importance of this ques-
rounding a specific fiber type is between 3-4 for ST tion is that although it is commonly believed that the
fibers and 2.5-3 for FTa and 2-3 for FT b fibers, Not diffusion of oxygen is the key factor, there may be
until the fiber size is taken into account can a signifi- situations during exercise where substrate uptake,
cant difference in capillarization of the various fiber release of a metabolite, or heat dissipation is just as
types be established. In the untrained muscles studied essential.
the average area a capillary supplies is 20%-30% more
for FT b and 10%-20% more for FTa than for ST fibers. Capillary Length and Diameter
The absolute values may vary markedly between in-
dividuals and also between muscles but the overall There are few detailed studies on capillary length
pattern is remarkably stable. What contributes to this and diameter for most species, and for man they are
rather small difference is the fact that in large parts of nonexistent. Thus available information on capillary
mixed muscle, FT fibers share capillaries with adjacent surface area and volume in skeletal muscles is limited.
ST fibers. In locally homogeneous areas of mixed In the early studies the capillaries were estimated to
muscle where an individual muscle fiber is surrounded account for 10% or more of total muscle volume, which
only by those of similar type, it was found that there was much too high a value as could be deduced from
are 1-4 capillaries per FT fiber but 4-11 capillaries per measurements oftotal vascular volume (535). Pappen-
ST fiber (G. Sjegaard, personal communication). Ac- heimer et al. (536) estimated the values to be approx-
counting for differences in fiber size, the ratio for the imately 0.1 of those previously reported; i.e., capillary
fiber-type area each capillary had to supply could be surface area was estimated to be 0.7 m 2 j 100 g muscle
estimated to be in the order of 3:1 for ST and FT tissue and the volume 1.6%. Later studies have all
fibers, respectively. The value found in human muscle given estimates of the same order of magnitude al-
is not much different from similar calculations made though there appears to be some variation related to
by Renkin and co-workers (285, 575) on rabbit muscle. species and muscles studied (111, 285, 492, 728).
It must be reiterated, however, that such extreme The most direct measurements are obtained with
differences are rarely seen in human muscles since vital microscopy. In the rabbit's tenuissimus muscle
especially FT (FT b ) fibers are seldom surrounded only the diameter averages 5.4 !-tm and is slightly narrower
by fibers of the same type. at the arteriolar end of the capillary [4.7 urn (196)].
The concept of a coupling between aerobic potential Cat tenuissimus muscle capillaries have the same di-
of the muscle and its capillary supply has been chal- ameter, whereas those of the dog gastrocnemius (4.2
lenged by Maxwell and colleagues (482). They studied um) and rat extensor hallucis proprius (4.8 !-tm) are
fiber composition, oxidative potential of whole muscle, slightly smaller (477, 507). Length of muscle capillaries
and degree of capillarization of various skeletal mus- varies markedly in the same capillary bed, and by
cles from five species and found no significant relation comparing various muscles and muscles in various
among any of the variables. This conflicts with a large species figures between 100 !-tm and 2,000 !-tm have
number of other reports, but it must be pointed out been reported (196, 507, 509). Assuming a length of
that Maxwell et al. did find significant correlations 1,000 !-tm for mean capillary length in human muscle
among several ofthese variables within a species (482). and a mean diameter of 6 !-tm (slightly less than the
The metabolic potential of a given muscle fiber type mean diameter of a red blood cell), this will give a
may vary considerably between species, and indeed capillary surface area of 0.62 cmt/cm" muscle in a
may vary within a given animal. Thus the approach muscle with 330 capillaries/mm", In muscles with pre-
taken by Maxwell et al. may not be the most fruitful dominantly FT fibers this value may be slightly less
to elucidate the problem of a coupling between aerobic and in muscle with many ST fibers somewhat higher.
potential of a fiber and its capillary supply (482). Based on the same assumptions capillary volume in
From among variables used to quantitate capillari- human skeletal muscle is around 1%.
zation, the question of which serves as the best indi- In these estimations of capillary surface area and
cator of diffusing conditions is still unsettled. Based volume it is usually assumed that the capillaries are
on a comparative study of various species, Plyley and straight, as the most precise numbers for length and
Groom (561) have come to the conclusion that the diameter of the capillaries are obtained on thin and
number of capillaries per fiber is an appropriate meas- flat muscles. The capillaries may have a rather tor-
ure, whereas others favor Krogh's concept of a capil- tuous arrangment, especially in muscles with many
lary and its "diffusing" cylinder (6, 226, 295). Although ST fibers. Thus an underestimation of the true surface
it appears essential to include an estimate of diffusing area and volume of the capillaries is likely in these
distance, it is not immediately apparent whether the muscles. All of these estimates concern the total num-
critical distance is to the center of the muscle fIber or ber of capillaries in a muscle, only a small fraction of
606 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

which may be exposed to circulating blood at any types and the size of the fibers are increased (6, 402,
given time. 523). However, the increase in capillaries is larger than
the increase in fiber size resulting in a definite reduc-
tion in the fiber-type area each capillary has to supply
Use and Disuse (Fig. 26). The present reduction in diffusing area is
CAPILLARY DENSITY. Long before systematic studies found to be largest for FT (FT b ) fibers. This is quite
of the effect of training on skeletal muscle capillariza- similar to the observation for the activity of mitochon-
tion were performed, it was noted that the domesti- drial enzymes. In untrained muscles FT (FTb ) fibers
cated animal held in sheds or cages had fewer skeletal have the largest fiber area per capillary and the lowest
muscle capillaries than its counterpart living in the level of oxidative capacity, but with use these fibers
wild (65, 710). Early training studies on rats also adapt and become almost indistinguishable from ST
revealed a pronounced increase in the number of skel- fibers for these variables. This supports the concept of
etal muscle capillaries, although the significance of Romanul and others (569, 588, 590) that there is a
some of these early reports can be questioned as close coupling between the number of capillaries and
exceptionally high capillary counts were observed. No the capacity for oxidative metabolism of the fibers
doubt exists, however, that there is a true proliferation they supply. Further, in experiments where the time
of capillaries associated with an enhanced physical course for changes has been followed in rat and rabbit
activity level in these nonhuman species (for refer- muscle during chronic stimulation, it appears as if the
ences, see ref. 370). Further, the adaptation is a local capillaries begin to proliferate before changes can be
response, i.e., it occurs in the exercised muscle and noted in the oxidative enzymes. Just as importantly,
only around those muscle fibers that are recruited in it proves that the FT fibers have the ability to adapt
the training schedule. to aerobic metabolism, which is similar to the metab-
For a long time comparable data were not available olism of ST fibers.
in man. In the first systematic study, cross-sectional In the experiments with chronic stimulation of a
material of sedentary men and endurance athletes was muscle it was found that along with enhanced aerobic
examined, and the same number of capillaries per fiber potential of the muscle fibers and increased number
was observed in both groups (342). Further, in a study of capillaries adjacent to a fiber, the fibers also became
where the physical activity level was varied, no sig- slightly smaller, thereby contributing to the shortening
nificant changes in any of the variables to stimulate of diffusing distances in the muscle (134, 135). Also,
capillarization could be detected (601). In both ofthese with endurance-type training in animals as in stan-
studies electron microscopy was used to identify the dard-bred horses and rats, the mean muscle fiber area
capillaries. Judged by the low numbers of capillaries is reduced in trained muscles [(110, 204); unpublished
per fiber reported by these investigators, all capillaries observations by P. Henckel on horses]. This reduction
may not have been identified. is mainly a function of smaller FT (FG and FOG)
More recent studies using both electron microscopy fibers. Similar findings from man are available. In
and histochemistry have demonstrated that human well-trained endurance swimmers, mean muscle fiber
skeletal muscle adapts to use by increasing the number area was the smallest in the most trained muscles
of capillaries (6, 73, 385, 387, 402, 521, 523). In fact all (523), and in marathon runners the areas of muscle
variables (capillaries per fiber, capillaries per square fibers in the gastrocnemius muscle were also small
millimeter, and number of capillaries found around a (367). Further, 2 wk of no training caused the muscle
fiber) are increased. As the latter two variables also fibers of the gastrocnemius to become slightly larger
are a function of muscle fiber size, the variable most (367). These findings may support the notion that the
frequently used is capillaries per fiber. This indicator distance to the center of the muscle cell is a critical
of capillarization is in trained muscle closely linked to factor. Whether it is the transport of gas or substrate
whole-body maximal oxygen uptake of a subject (Fig. that is crucial is, however, still obscure. Because
25), and alteration in activity level causing a change in myoglobin markedly enhances the oxygen transport
maximal oxygen uptake results in a parallel change in within the cell (724) and is elevated with enhanced
the number of capillaries per fiber. From such plots it oxidative capacity, the reduction in diffusing distances
is apparent that the percentage changes of these two of substrates other than oxygen may be the crucial
variables are comparable. A doubling of maximal ox- limiting factor. .
ygen uptake corresponds approximately to a doubling The effect of inactivity on muscle capillarization is
of the number of capillaries per fiber. Including the less well studied in man (Fig. 26). The picture that
size of the fibers in the evaluation of diffusing condi- emerges from available detraining studies or studies
tions of skeletal muscle with training makes the pic- where a limb is placed in a cast is that the number of
ture somewhat more complex but also gives a deeper capillaries per fiber is reduced. Notably it appears as
insight into the problems. In most training studies of if early in the time course the reduction in the number
the endurance type, skeletal muscle fibers are slightly of capillaries is slightly slower than a possible change
enlarged. If in the exercise all fiber types are involved, in fiber size, resulting in slightly shorter diffusing
both the number of capillaries around the various fiber distances the 1st wk of inactivity (605). After some
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 607

3.4

3.0 r.
o 2.6

r
T
. 1
I I II 1
nI
'-22
II .

II
-
'-
.0

II
;;: 1.8
! 11
d
>-

I
'-
.!! 1.4
'Q.
nI
u 1.0 1
0.6
~i'-"''------'-_---'--_....I...-..----'_---'--_......L...-_-'---------1_----'-_....L.-_
'30 35 80

FIG. 25. Capillaries per muscle fiber related to maximal oxygen uptake. Diagram includes mean
values obtained from the following: PAS method, light microscopy (PAS + LM) studies, open symbols
(5, 6, 521, 523), and electron microscopy (EM) studies, closed symbols (73, 385-387). Circles, females;
triangles, males. P = 0.001; r = 0.917. [From E. Nygard and H. Schmalbruch, unpublished observa-
tions.]

weeks both variables approach a new level of adapta- ment of the aerobic enzymes (537). Further, an in-
tion (425). With tenotomy, reduction in capillary den- crease is only observed in muscles engaged in the
sity has also been observed (411, 412). training program. Studies on human muscles are
scarce. In preliminary reports by Jansson and Sylven
CAPILLARY LENGTH AND DIAMETER. The only exact
(400) a clear-cut difference was observed when ST and
data available are from studies on rats and rabbits,
FT fibers were compared, with the mean value for ST
where muscles have been chronically stimulated and
fibers being 60% higher than for the FT fibers. So far,
evaluated with vital microscopy (509). Along with a however, they have been unable to detect a training
quite rapid proliferation of capillaries, which is notice- effect, i.e., when examining cross-sectional material of
able within days, there is a reduction in mean capillary trained bicyclists with sedentary people, the same
length. The increase in number of capillaries is larger myoglobin content is noted in the leg muscles although
than the decrease in length. The capillary surface area a difference in mitochondrial enzyme is noted (E.
and volume do enlarge with increased use of the Jansson, personal communication).
muscle. Further, the diameter of the capillaries is
increased and may amount to 1 IJ-m in the arteriolar
end and 2.3 IJ-m in the venular end of the capillary. Regulation
In addition to increased branching, as a result of
more muscle activity the capillaries may become more Little is known about the factors involved in capil-
tortuous (13). Precise data on this point are not avail- lary proliferatioh. Myrhage and Hudlicka (509) cite
able, however. Ashton (20) saying that "endothelial cells themselves
are in some way directly sensitive to oxygen-multi-
MYOGLOBIN. The redness of a muscle fiber depends plying at low O2 levels, resting at normal O2 levels, and
on its myoglobin content, and for a long time this has dying at high Oe concentrations." They base this belief
been the basis for classifying muscle fibers. The oxi- in tissue partial pressure of Oz (Po-) being the crucial
dative capacity of the muscle fiber and its myoglobin variable on the same reports of high capillary counts
content are closely coupled in a large range of animal in skeletal muscle of animals living at or exposed to
species (448-450). With physical training in rats myo- high altitude (14, 112, 699). Other studies have re-
globin content is increased parallel to the enhance- vealed that it is questionable whether any new capil-
608 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

Capillariesl damage or inflammation are observed (509). Because


muscle fibre area sprouting capillaries are most frequently found
1.3 number branching off where the capillary is bent and its di-
~m2. 10 3 ameter widens (509), the pressure in the capillaries
r-- both at arteriolar and venular ends may serve as
1.2 stimulus for proliferation. This hypothesis is, however,
not experimentally tested.
- SIGNIFICANCE OF ADAPTATION

In this section we analyze what the specific role may


1.0 be for the adaptations that occur in skeletal muscle as
r--
r-- a result of changes in patterns of use and disuse. More
0.9 - specifically the focus is on how these may alter metab-
olism and performance. A schematic overview of the
r-- varying systems and the interaction between them is
0.8 given in Figure 28. We briefly sum up the possibilities
that exist for each of the essential adaptations under
study and discuss their contribution to a change in the
0.7
r--- """" f--- f--- ...... I- metabolic response to exercise. Further, we evaluate
A B C o N
whether such a change would aid in explaining a
change in performance capacity. Finally, we feel that
Vo 2 m ax it is equally important to discuss why certain adapta-
mllkg. min
tions do not occur in spite of the fact that at first
40 47 54 74 46 35
glance they would appear likely and beneficial.
FIG. 26. Mean values for number of capillaries per 1,000 p.m of
2

muscle fiber area. Bar A shows results from a group of sedentary Muscular Size
subjects (602). Bars Band C show values before and after 8 wk of
conditioning (6, 425). Bar D shows values from well-trained men The capacity of skeletal muscle to develop tension
(367,398,523,602). Bars M and N are values from subjects decon-
ditioned for 7-14 days (ref. 425; B. Saltin, unpublished observations).
per unit of cross-sectional area is not altered by train-
V02 max below bars M and N was estimated from heart rate response ing. At the molecular level this implies that the tension
to submaximal exercise (subjects were recovering from minor knee developed per cross-bridge interaction is constant.
injury). This is what could be anticipated. A large variation
does exist in the number of fibers contained in the
laries are formed when exposed to low oxygen pressure same muscle of man and rat. This is probably a func-
in inspired air. Systematic studies in various species tion of genetic endowment and a likely factor in lim-
by Banchero and associates (30, 164, 631, 632, 635) iting the maximal growth potential of a muscle. As
clearly demonstrate that the larger number of capil- fiber number is uninfluenced by the activity level, the
laries per square millimeter is due to the decrease in only resource available for increasing total muscular
the cross-sectional size of the muscle fibers. The num- strength is for the muscles to increase in cross-sec-
ber of capillaries per fiber is unchanged in their stud- tional area (427). This is accomplished by a hypertro-
ies. The same appears to be true for human muscle phy of the existing muscle fibers. It may appear that
(604). When sea-level residents stay at high altitude it would be just as logical to have mechanisms for
(elevation 3,700 m) for months, the muscle fibers be- increasing the number of fibers in a muscle rather
come slightly smaller but the number of capillaries per than restricting the number of those present either at
fiber is unchanged (Fig. 27). Further, permanent resi- or shortly after birth. There are, however, a number
dents at this altitude do not have a high number of of arguments against the efficacy of adding fibers to
capillaries per fiber, but they have small muscle fibers preexisting muscles. First, this could disturb the exist-
resulting in high values for capillaries per square mil- ing architecture in the muscle by having to provide for
limeter. When the high-altitude residents are divided new attachments on the bone or tendons that serve as
into physically inactive and physically active, the lat- origin and insertions. If the fibers arose within the
ter group has the higher number of capillaries per muscle without appropriate attachments they would
fiber, similar to the results found in sea-level residents. be ineffective (506). Second, and perhaps of greater
Thus it appears likely that tissue oxygen tension is not importance, is the problem of how they would be
the key factor for capillary proliferation. innervated and incorporated into preexisting motor
Unfortunately no other obvious alternative for a units. A lateral sprouting of the existing motor units
stimulus and regulatory factor has been suggested. In might also result in reducing the capacity for neuro-
tissue injury some substance is thought to be released, muscular coordination.
serving as a stimulus for capillary proliferation (68); Although the capacity for skeletal muscle to enlarge
but with increased use of a muscle, no signs of tissue appears to be great, there may not always be a direct
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 609

~ Fibre area
,um 2 x 10
3
fibre

no.
5.5
2.2

2.0 5.0
FIG. 27. Capillaries per fiber and fiber area in
sea-level residents at sea level and after an average
32 wk (6-52 wk) at elevation 3,500 m and in high-
1.8 altitude residents. For further details see Fig. 23.
4.5 [Adapted from Saltin et al. (604).]

1.6
4.0
1.4
l' ioirs
Sea level Hlgll altitude Sea level High altitude
residents residents residents residents

I2a Sea level urn Sedentary

~ Altitude Physical active

ENERGY STORES METABOLIC PATHWAYS

f-----.....,~Embden-Meyerhof

~Li pids
------'

ENDURANCE
OXYGEN DELI VERY

r Lung H(:ardlovasc~lar
FIG. 28. A schematic summary with indication of relative importance of various energy stores and
metabolic pathways for performance in strength, sprint, and endurance events. Included in the scheme
are also indications of how oxygen delivery and the nervous system are interacting.

relationship between the degree of enlargement and tendon. A mathematical model illustrating this prin-
the torque that a muscle can develop around a joint. ciple was published by Lindhard (456). Although in-
This is because for muscles with pennate fiber arrange- creases in strength can be closely related to changes
ments the angle of attachment to the tendon becomes in the total cross-sectional area of a muscle, there are
greater as they are enlarged (57,490). Since the force many reports of increases in muscular strength with-
developed along the long axis of the muscle depends out changes in muscle bulk. This can be explained on
on the angle of attachment, this change in angle will the basis of an increased capacity for motor unit
result in a diminution in the tension transferred to the recruitment and activation.
610 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

Substrate Stores ever, cannot be sustained for this period of time, and
factors other than the local availability of substrate
The resting levels of ATP and CP in skeletal muscle must be limiting. Thus it would appear that augment-
of man are in the range of 5 and 20 mol/kg wet wt, ing the local energy stores, whether this be as glycogen
respectively, and these stores are influenced by the or triglyceride, would be of little importance for max-
state of training only to a very minor extent. The imal efforts. With short, intense exercise there is a
amount of energy contained in the phosphagen stores rapid depletion of glycogen from the FT fibers in
is very small and would only support 3-4 s of maximal skeletal muscle. A failure to sustain multiple bouts of
contractile activity. With a few exceptions even a such exercise may be related to an exhaustion of the
doubling of these stores would have little physiological local glycogen in the FT fibers. An elevation in the
meaning. Instead it would be more judicious to enlarge glycogen stores could forestall exhaustion in such ac-
the capacity for resynthesizing ATP through an in- tivities.
creased capacity for energy release via end-terminal A second aspect of the importance of changes in
oxidation and/or glycolysis. intramuscular energy stores relates to submaximal
That the energy per unit of weight in ATP and CP exercise. As indicated, the exercise capacity of man at
is quite small supports such a conclusion. Further, by power outputs of about 50% of maximal is several
keeping the ATP-ADP-AMP pool low in muscle, any hours. The immediate energy stores of muscle are
changes among these components result in a large sufficient for up to 200 min of such exercise. Thus it is
change in their ratio, which is important in view of the obvious that extramuscular substrates also are impor-
regulatory function this ADP/ ATP ratio has on the tant. This has been demonstrated in experiments
metabolic reactions both in the cytosol and in the where mobilization of fats has been inhibited. At ex-
mitochondria. haustion the carbohydrate stores of the body are
The glycogen stores of the muscle are only slightly nearly depleted (341), and the importance of this en-
elevated as a result of changed activity level. Any ergy store as a determinant of exercise capacity has
specific role of this increase for brief exhaustive exer- been demonstrated (51,222,260,577, 725). Consump-
cise, where muscle lactate reaches levels of 20-25 tion of a fat and protein diet decreases exercise toler-
mmol/kg wet wt, can hardly be anticipated, as muscle ance by about 25%, whereas exercise capacity was
of sedentary man already contains approximately 80 doubled following consumption of a high-carbohydrate
mmol/kg wet wt of glycogen. In repeated efforts a high diet (51, 271). Subsequent experiments have estab-
initial glycogen storage may be of some importance. lished that these dietary manipulations alter the gly-
The question can then be asked, how important are cogen store of the muscle and that a linear relationship
changes in the intramuscular energy stores in terms of existed between exercise capacity and the muscle gly-
the capacity for aerobic energy production? This can cogen concentration (51). The role of stored triglyc-
be considered from two standpoints. First, how would eride is unknown. It is, however, well known that
an augmentation of the local energy reserves relate to increases in the local glycogen store can increase ex-
the maximal work capacity of a muscle if this were the ercise capacity. This is even more important when
only source of substrate? The aerobic capacity of coupled with the increased oxidation of fat that occurs
skeletal muscle is a function of the maximal flux of with training.
substrates through the oxidative systems of the mito-
chondria and the supply of oxygen. The maximal Enzyme Activities
substrate flux through the metabolic pathways can be
estimated from the V max of selected enzymes (see ANAEROBIC METABOLISM. There are reports of in-
Table 1). From such data it can be estimated that the creases in the activities of some enzymes in the gly-
maximal substrate flux through the oxidative enzymes colytic pathway. In some instances these changes are
would require an oxygen uptake of about 850 ml- kg-I. small and appear to exist in only select enzymes of the
min- I and a blood flow of about 5 liter-kg r'<min" system. Moreover in some cases the enzymes that
(based on an oxygen extraction of 170 ml /liter of have been reported to increase are not those whose
blood). If this oxygen uptake can be attained by man activity is known to be regulated (PHOS, PFK) and
it is only with exercise of a small muscle group (1). which thus exert control over the flux of substrate
With exercise (such as walking, running, or cycling) through the system. Overall the data available con-
that is sustainable for 8-10 min, the oxygen consump- cerning adaptations in the glycolytic system are less
tion may average about 150 ml/kg of active muscle certain than those for the enzymes for end-terminal
per minute. When the exercise intensity is about one- oxidation.
half that sustainable for 8-10 min, it can be performed An increase in the enzymes for glycolysis has an
for many hours. If fully oxidized, the glycogen and unknown role in the overall economy of the metabolic
triglyceride stores of human muscle are equal to about response to exercise. All fiber types are very well
200 and 80 kJ/kg wet wt, respectively. At the maximal endowed with such enzymes. For example, the PFK
rate of oxidation with a small muscle group, the local activity of the ST and FT fibers of human muscle has
energy stores would last 17-18 min. Such efforts, how- been reported to be 25 and 50 mmol.kg-I.min- I (203).
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 611

This enzyme usually has an activity similar to that of concentrations of enzymes exist in the glycolytic path-
PHOS. Both enzymes are regulated and are generally way. These levels are obviously higher than would be
believed to regulate the flow of substrate through the required to produce the substrate flux that occurs
glycolytic pathway. If fully activated this would result through this pathway. It would appear that the answer
in the production of 50 and 100 mmol Iactate-kg": lies in the overall regulation of this system. There are
min" for the ST and FT fiber, respectively. These rate-limiting enzymes in this pathway. However, most
values far exceed those that have been observed during of the enzymes are of the equilibrium type and obey
maximal voluntary muscular activity. It has been es- Michaelis-Menten kinetics and thus are substrate con-
timated that a 5% activation of PHOS could account trolled (Fig. 29). With such enzymes the higher the
for the maximal lactate production in skeletal muscle enzyme concentration the greater will be the activity
if glycolysis depended on PHOS (220). Further aug- at very low substrate concentrations. This allows for
mentation of this system would not seem useful. More- a better control over the system. For example, with an
over it does not appear that increasing the total enzyme such as pyruvate kinase the activity of which
amount of enzyme available would increase the pre- is about 400 {.tmol of substrate converted per gram per
cision for regulating substrate flux through the system. minute, it is highly unlikely that a substrate concen-
As pointed out, the concentration (activities) of the tration could ever be reached to produce Vmax. How-
enzymes of the Embden-Meyerhof pathway is very ever, a low substrate concentration, for example, 10%
high in most skeletal muscle, particularly in the FT of the K m , would induce an activity of about 40 umol
fibers. This activity would appear to be greater than of substrate split per minute per gram. This activity is
that which would ever be required for the degradation higher than that required for the maximal rates of
of glycogen. This brings up the question of why these lactate production that occur during heavy exercise.
enzymes are maintained at such high levels. This With high enzyme levels it is possible to attain high
metabolic pathway would be most important during rates of substrate fluxes at low substrate concentra-
periods of short, intense muscular activity where a tions. Since there are a number of enzymes involved
major part of the ATP production was derived from in the pathways for ATP production, the induction of
the degradation of glycogen to lactate. During such high activities via elevations in substrate levels would
activity lactate concentrations in muscle and blood in
excess of 20 mM are frequently attained (265). It has
been suggested that such high lactate concentrations
Vmax at 2 X enzyme conc.
would interfere with subsequent efforts, either by low- -------- --- ---
ered pH or by end-product inhibition of enzymes (417).
The low pH could affect the oxidative system and the
glycolytic pathway. If so, attempts at repeating high-
intensity efforts would be characterized by a reduced
exercise tolerance, a decrease in the VO Zmax, and a
decline in total lactate production. With such repeated v
o
efforts V' OZmax is reached earlier, however, and there is CIo
a continued elevation in the blood lactate. This sug- >
gests that lactate per se is not responsible for termi- c:
o
nating the exercise, nor are the enzymes for metabo- v
lism significantly inhibited.
a:'"
CIo
The question of whether the lactate levels as seen
in the blood and muscle of man after short, high-
intensity exercise could inhibit a further degradation
of glycogen can also be asked. Some information re-
lating to this possibility may come from studies of
diving mammals. The glycolytic enzyme levels in these
animals are not conspicuously different from those of Sub s t ra t e c o nc e n t r at i cn in rnore s r l
man (432). When these animals dive there is an almost
complete shunting of the blood from the peripheral FIG. 29. A representation of the influence of changing the total

muscles to the heart, lung, and brain circuit. The enzyme concentration on the specific activity based on the rate (V,).
The velocity and any substrate concentration [S] can be estimated
exercising muscles may be nearly ischemic. Muscular from the Michaelis constant (K m) and the maximal velocity (Vmax)
activity can continue for rather long periods of time
under these conditions. After such exercise the muscle for the equation V, = Km[:][S]' Vmax. With a doubling of enzyme
lactate may exceed 50 mmol/kg. This suggests that an concentration, velocity of the reaction will be doubled at any sub-
end-product inhibition of the glycolytic pathway prob- strate concentration. This relationship would be most important at
low substrate concentrations where substrate could thereby be more
ably does not occur or is of only minor importance in efficiently directed into end-terminal oxidative pathways. Con-
those animals. versely with a reduction in enzyme concentration such control
The question remains as to why the very high would be lost. [From Gollnick and Saltin (256).]
612 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

% Change Leg
< ~
160"/0
Systemic
60 ,.. ( ) 60
.-----
Leg -
E )

.----- t---
40
40

Systemic
20 ( )
.----- 20
.-----
.-----

+ Blood Oxid Oxid +


V0 2 6 ~~;~ flow ~-vO:l Cap. enz. V0 2 Q a-~~-~9l
diff. dltt. Cap. enz.

A B
FIG. 30. Summary of changes associated with a moderate (paneIA) and a large (panel B) increase
in V0 2 max in response to physical conditioning. A: from longitudinal studies in which sedentary
subjects were conditioned for 2-3 mo. B: (also longitudinal studies) subjects participated either in a
conditioning program for 2-3 yr starting from a sedentary level [V02 max 45 ml-kg i'vmin" (184)] or in
an intense conditioning program for some months starting from very low V0 2max [34 ml 02kg- l
min" (601)]. [A: circulatory data: (184,594,601). Leg blood flow and arteriovenous O 2 differences are
collected from several studies: (408, 603, 711) and B. Saltin, unpublished observations. Muscle data:
(338) for enzymes, (8) for capillaries. B: central circulatory data: (184, 601). Leg arteriovenous O2
differences: (601); muscle capillarization and enzyme data are from unpublished studies by B. Saltin,
J. Halkjrer-Kristensen, and T. Ingemann-Hansen.]

increase the particle level to a point where the osmotic variations in training studies, many researchers use it
pressure within the cell would be unacceptable. as a criterion to illustrate the importance of these
variables in attaining maximal oxygen uptake.
AEROBIC METABOLISM. In addition to substrate levels It is true that many links in the transport of oxygen
and mitochondrial enzymes, the role of oxygen deliv- to the tissues are closely related, but this does not
ery is important for a discussion of the aerobic energy mean that they are limiting (63, 636). Exercise with a
yield in muscle. To thoroughly discuss this subject we single muscle group, such as the knee extensor mus-
need to summarize some of the adaptations that occur cles, illustrates this problem. In a sedentary person
within the cardiovascular system as a response to blood flow to these muscles at maximal exercise may
varied levels of physical activity. From the results in average 2,000-3,000 ml- kg- I of muscle. min -I, V02may
Figure 30 it is apparent that at maximal exercise attain values of 400-500 ml 02kg- 1 of muscle.min-I,
(running or bicycling) that elicits maximal oxygen while the arterial-femoral venous oxygen difference is
uptake both systemic cardiac output and a widening maintained at around 160-180 ml/liter (1). Thus when
of the arteriovenous difference contribute to the im- the capacity of the cardiovascular system can be di-
proved maximal oxygen uptake. After a short period verted to a small, maximally activated muscle mass,
of adaptation to endurance training these two factors considerably larger blood flow and oxygen uptake
increase to the same extent. After a longer period of (milliliter per kilogram of active muscle) are observed
training, enlargement of the cardiac output contrib- than in ordinary whole-body exercise when systemic
utes the most to the increased maximal oxygen uptake. cardiac output is shared by a much larger muscle
Muscle capillary density and mitochondrial enzyme mass. Although blood flow through the knee extensors
activities are enhanced both after shorter and longer is tremendous, an extremely wide arterial-femoral ve-
periods of adaptation. The percentage increase in cap- nous oxygen difference is maintained. Taken in total,
illarization occurs in parallel with maximal oxygen we conclude from these results that neither the capil-
uptake, whereas the increase in mitochondrial enzyme larization of the muscle nor the concentration of mi-
potential is far in excess. The question then is whether tochondrial enzymes are limiting to whole-body aero-
these changes in the muscle are necessary to increase bic power in healthy man.
maximal oxygen uptake. Since close relationships exist If we cannot ascribe any significant role to the
among the degrees of capillarization, the activity of a adaptation in capillarization or mitochondrial enzyme
marker enzyme for oxidative capacity, and maximal concentrations for attainment of maximal oxygen up-
oxygen uptake in experimental material with large take, why do these variables change so dramatically
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 613

in response to physical training? An obvious effect of importance, and most enzymes function at most at
increasing the number of capillaries, and also the about 50% of the Vmax or near the K rn in the intact
observed small decrease in the size of the muscle fibers system. Another illustration of this concept is that to
with extreme endurance training, would be to reduce elicit an increase in the enzyme velocity from 10% to
the diffusion distances within the muscle. This may 90% of the Vrnax requires an 81-fold increase in sub-
be crucial for gas and substrate transport, especially strate concentration. Such a flooding of the tissue with
FFA, from the blood to the muscle cell. any metabolite is extremely unlikely. However, an
In the trained state the number and volume of elevation in the total enzyme concentration would
mitochondria increase, which increases the surface increase the sensitivity for control at low substrate
area for the exchange of metabolites, cofactors, and levels and also increase total activity. This could result
end products between the cytosol and the mitochon- in a more efficient use of the substrate stores by
drial matrix. Of particular interest here might be an directing them through the oxidative pathways with
increased capacity for the transport of fatty acids into the result being to maintain a constant ADP/ ATP
the mitochondria and the ATP out into the cytosol. ratio in the cytoplasm thereby inhibiting anaerobic
This could in part be responsible for the increased use glycolysis at the level of PFR. Such a fine tuning of
of FFA, the decreased rate of glycogen depletion, and the control of oxidative metabolism could be respon-
the lower lactate levels that occur in response to a sible for the lower respiratory exchange ratio and
standard exercise test after training. These differences lactate levels in muscle and blood that occur during
occur despite lack of change in oxygen uptake and exercise after training. Conversely a decrease in phys-
cardiac output at standard work loads before and after ical activity with a resultant loss of oxidative capacity
training. would have an opposite effect on metabolic control.
A possible effect of increasing the activities of oxi- Could the increase in the enzymes for oxidation be
dative enzyme in muscle would be to elevate the operative in controlling the entry of substrates into
capacity for the low oxidative fibers for terminal oxi- the citric acid cycle? The key enzyme for such sub-
dation. Thus the FT fibers, and particularly the FT b strate entry is thought to be citrate synthase (722).
fibers, could more effectively utilize the intracellular The activity of this enzyme increases with endurance
glycogen stores and perhaps rely to a greater extent training; it is also regulated by the levels of both
on the oxidation of FFA during prolonged exercise. acetyl-CoA and oxaloacetate (722). This is not to imply
This would be important where such fibers ultimately that substrate flux through the citric acid cycle is
are recruited during prolonged exercise, and during under such simplistic control but only to point out
more intense exercise, where there may be engagement that an increased enzyme concentration would facili-
of these motor units from onset of exercise. tate this control. It is known, for example, that the
Although the above considerations might be impor- flux of substrate through the citric acid cycle is a
tant for the understanding of the overall metabolism function of the coordinated control of citrate synthase,
of skeletal muscle during exercise, they fail to ade- isocitrate dehydrogenase, and a-ketoglutarate dehy-
quately explain why there is such a large increase in drogenase (722). These activities are linked not only
the oxidative capacity. The answer to this question to oxaloacetate and acetyl-CoA concentrations, but
could be related to how enzyme concentration influ- also to the NAD/NADH ratio and citrate levels. When
ences the sensitivity of enzyme regulation. Thus with the NADH level in the mitochondria is high, due
higher enzyme concentrations it would be easier to either to a lack of oxygen or to ADP, isocitrate dehy-
regulate the oxidative system on the basis of a sub- drogenase is inhibited and citrate accumulates. Such
strate and cofactor regulation of the enzymes. This an elevation of citrate concentration results in an
effect would be important for both the nonrate-Iimit- increase in the K of citrate synthase. With the oxi-
ing and the rate-limiting enzyme reactions. The un- dation of NADH the citrate level will fall and the K rn
derlying principle is that most enzyme reactions ap- of citrate synthase will be lowered. The increased
pear to obey Michaelis-Menten kinetics (256). Under enzyme concentration would aid in the directing of
these conditions increases in substrate exert profound acetyl-CoA units derived either from decarboxylation
control over the reaction rate at the lower levels of of pyruvate or /i-oxidation into the citric acid cycle.
substrate (Fig. 29). The substrate concentration that Since most of the enzymes of the citric acid cycle have
produces 50% of the V rna x is the well-known Michaelis been shown to increase in skeletal muscle in response
constant (Krn ) . This figure illustrates that by doubling to training, the overall effect would be to increase the
the enzyme concentration the reaction velocity at K rn response of this system to lower substrate levels.
will also be doubled. This is true since K rn is independ- The question can be asked, why would an organism
ent of enzyme concentration. Further, at very low adapt to an increased metabolic demand by increasing
substrate levels large differences in the reaction rate the level of proteins that would require energy for
in response to a given substrate concentration would synthesis and maintenance rather than by simply stor-
be realized by increases in total enzyme content. Since ing more intramuscular substrates? In the latter in-
the substrate levels needed to attain V rna x for a given stance it might be possible to raise the metabolite
enzyme are probably never attained in vivo, the ab- levels during periods of maximal activity to attain
solute V rna x for a given enzyme is probably of minor close to V max of the enzymes. Part of this answer lies
614 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE

in the fact that the substrate levels needed to attain ulation) and with the predominant fraction of the
V max of the enzymes are unreasonably high and might lipids stored outside the muscle cell, the ultimate
cause an increase in osmolality. In such a case this factor that determines the intensity and duration of
could be complicated because the intramitochondrial work is the body's capacity to utilize extramuscular
and cytoplasmic metabolic reactions may occur at fat stores. There are at least five steps required for the
different rates. Just as important is the possibility that transport of FFA from the adipocytes to the skeletal
glycogen, although it contains rather large amounts of muscles, where the lipids are being finally oxidized in
energy per unit weight, will create a weight distur- the mitochondria. These are 1) the release from the
bance because it is stored with 2-3 g of water per gram fat cell, 2) transport to the muscle via the blood, 3)
of glycogen. Migrating birds and insects have a metab- transport from the capillary across the interstitial
olism almost completely geared to fat metabolism space to the muscle cell, 4) transport into the muscle
(719). It is likely that in terrestrial animals the overall and mitochondria, and 5) oxidation by the mitochon-
economy of movement calls for limitation in the stor- dria. Both in the untrained and in the trained state
age of glycogen. the mobilization of lipids appears to be sufficient, and
The stores of lipids in human skeletal muscle are the exercising muscles are offered ample amounts of
rather small and no changes due to increased physical FF A. Only a very small percentage (3%-5%) of the
activity levels are apparent. Why this energy source is FFA that is offered by the blood is taken up by the
kept so low in the muscles of man and rodents is muscle (258, 269). This is also true in situations lacking
presently unknown. Instead, especially in man the all other substrates, indicating that the limitations in
extramuscular lipid stores are high and would, in in- the utilization of FFA lie either within the muscle or
dividuals of normal body weight, support many hours, in the transport of the FFA from the blood into the
in fact days, of submaximal exercise. muscle cell (510, 591). There may be a larger FFA
In contrast, glycogen is stored only in small amounts uptake by trained muscle but if this is so, it is within
outside the skeletal muscles, the total in the liver being the methodological variation and thus has not been
only 40-70 g (373). The primary purpose of this gly- substantiated (332, 333). It is not known which of the
cogen store is to maintain blood glucose concentration three remaining possibilities for limiting the uptake of
as a continuous supply to the nervous system. Its role FFA by skeletal muscle is the most important. Pres-
for muscle is limited. In fact at least two regulatory ently, it appears that the transport of FFA through
mechanisms are brought into play during exercise to the interstitial space with its low protein concentration
minimize its uptake by skeletal muscle. These are a may constitute the major hindrance. For obvious rea-
reduction in plasma insulin levels and an elevation in sons (colloid osmotic pressure and hydrostatic pres-
the intracellular concentration of glucose 6-P0 4 , which sure balance over the capillary wall) interstitial protein
inhibits hexokinase and the phosphorylation of glu- concentration cannot be elevated. With training, adap-
cose needed for its transport across the cell membrane. tations take place on both sides of this hindrance, by
increasing the number of capillaries and by elevations
Summary in mitochondrial volume and the capacity for f3-oxi-
dation. The importance of these adaptations is illus-
The stage is then set. In submaximal exercise with trated in Figure 31, which shows that when subjects
limited amounts of glycogen (also after dietary manip- who have trained one leg exercise using both, the

SOH RQ (leg)
p mol E'S. 9 -1. mi n- 1
mmoles Lactate
l min Release
5 1.00
4.0

4 3.0
NT
3 2.0

2 1.0

!
I
T
0.90 0
rest 60min
I I I
0 1.0
T NT 10 30 min 50
FIG. 31. Succinate dehydrogenase activity (.umol.g- ' wet wt-rnin'") in trained (T) and nontrained
(NT) leg (left), respiratory quotient (RQ) values (middle), and release/uptake of lactate (right) for
both legs during a posttraining metabolic study. Means SE are given. Significant difference
between trained and nontrained leg (P < 0.05). [Adapted from Henriksson (332).]
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 615

utilization of FFA is greater and the production of oxidative capacity rather than in substrate storage
lactate less by the trained leg in spite of the fact that with training may lie in the fact that the total protein
both legs were offered similar amounts of oxygen and needed to produce a doubling of mitochondria and the
FFA. Of note is that the increase in mitochondrial oxidative enzymes is relatively small, amounting to
protein is maintained as long as the training stimulus only a few milligrams per gram fresh weight. Such an
persists. After termination of training the "excessive" increase appears to add very little to the overall bulk
metabolic apparatus is rapidly disassembled and the of the muscle and to produce no measurable disturb-
muscle returns to the nontrained state. ance of the ionic and osmotic balance.
Part of the answer to why increases occur in total

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