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
active fibers could then be identified from serial cross
sections stained by histochemical methods. The initial
studies were done with rats (176, 437, 439, 440), after
which similar data were added from cat hindlimb
muscle (97, 99, 101, 102). Because of their invasive
nature, these methods cannot be applied directly to
the study of motor unit properties in human skeletal
muscle.
However, some motor-unit mapping of human skel-
etal muscle has been done with electrophysiological
methods (237, 485, 486). Such studies have demon-
strated a remarkable degree of similarity in the organ-
izational pattern from human and animal muscle. The
general characteristics of the motor unit are enumer-
ated. 1) All fibers in a single motor unit are homoge-
neous with regard to histochemically identifiable con-
tractile and metabolic properties (237, 437, 441). 2)
The fibers in a motor unit are distributed in a fairly
large part of the cross-sectional area of the muscle
(10%-30% for the rat tibialis anterior muscle) (183).3)
Fibers belonging to a single motor unit are rarely
positioned immediately proximal to each other. 4) A
central locus for a motor unit exists with the density
of fibers in the unit declining as a function of the
distance from the center (176,440). In the cat gastroc-
nemius muscle, fibers belonging to 40 or 50 motor
units may be found in the same region (mm") of the
muscle (101). In man, there appear to be only 15-30
motor units contained in a 5- to 1O-mm2 cross-sectional
area (86-88). Motor units found in a given area can
belong to all of the types represented in the muscle.
Fibers per Motor Unit
Data are available on the number of fibers per motor
unit for a few muscles of several animals including
man. For some animal studies the glycogen-depletion
method was used to make these estimates. In others
the number of motoneurons entering the muscle along
with estimates of the total fiber number were used to
calculate this ratio. In the rat soleus, containing a total
of about 2,500 fibers, there are approximately 35 motor
units (297). The range of fibers per motor unit in the
rat is from 50 to 178 with a mean of 125 (176,438).
The tibialis anterior muscle of the cat has been re-
ported to contain 56,000 fibers (156). The range for the
slow-twitch (ST) motor units has been reported to be
from 469 to 1,323 fibers per motor unit with the
average being 775. For the fast-twitch (FT) motor
units the average was 169 fibers per motor unit with
a range of from 43 to 382 (156). In the studies of cat
skeletal muscle only a small percent of the total num-
ber of motor units was examined.
Data from man are quite difficult to obtain. The
most reliable estimates have come from counting the
total number of motor nerves and muscle fibers (115,
121, 216). Estimates based on electrophysiological
(485) measurements are less reliable. The range of
fibers per motor unit is from 110 for the lumbricalis to
1,720 for the gastrocnemius medius muscles (216). At
present there are no exact determinations of the num-
ber of fibers in the different types of motor units found
in human skeletal muscle.
Contractile Properties
The basic feature that differentiates motor units
into types is their contractile properties. These are
identified from the time to peak tension in a twitch
and the closely related one-half relaxation time. Two
general classes of motor units and in some cases of
complete muscles can be identified from these con-
tractile properties. One group of motor units possesses
a relatively long time to peak tension (a slow twitch)
and the other a short time to peak tension (a fast
twitch). Available data on the contractile properties
of various motor units or muscle fibers within a single
muscle illustrate the existence of a clear dichotomy of
contractile speeds between fiber types (98-102, 223,
437,438,540). A discrete dichotomy does not extend,
however, to the individual motor units, where there is
a wide range of contractile speeds in spite of similar
histochemical characteristics.
Biochemical Basis for Differences in
Twitch Properties
A prime determinant of the twitch property of mus-
cle is the rate at which myosin splits adenosine 5'-
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
specific activity of the pure protein is obtained without
the dilution effect produced by the presence of other
contaminating proteins. The relationship between the
specific ATPase activity of myosin and contractile
speed for a variety of muscles with varying twitch
times is presented in Figure 1.
The differences in the specific ATPase activity of
myosin are attributable to the existence of multimo-
lecular forms of the protein (76-78, 240, 242, 243, 351,
352,466,533). These polymorphic forms of myosin can
be identified and differentiated from a number of
physicochemical characteristics. The simplest method
for identifying the myosin isozymes is based on their
susceptibility to loss of ATPase activity in response to
changes in pH (77, 78). Myosin from FT muscles is
alkaline stable but acid labile (Fig. 2). The opposite is
true for myosin from ST muscles.
The multimolecular nature of myosin becomes a
feature of all of the components that are assembled to
form the functional protein complex (64a). This com-
plex is composed of both a heavy- and a light-chain
portion (463, 467, 655, 717). The heavy-chain portion
can be divided into the structural subunits of the rod
and the head. The ATPase activity is localized in the
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 head portion of the heavy myosin. Identification
of the components of myosin can be made through the
use of immunological methods used in conjunction
with histochemistry (Fig. 3). With these methods spe-
cific antibodies have been prepared against all sub-
units of the heavy chain and the individual light
chains. Two classes of slow and three classes of fast
ATP-splitting myosin have been identified with these
techniques (595, 596). In general each muscle fiber
contains only one class of myosin (that is slow or fast)
but the relative proportion of the different isozymes
in this class can vary. There are, however, instances in
which fibers may contain a mixture of classes of
myosin (421, 552, 715). These immunological methods
hold great promise for positively establishing the ex-
istence of a specific type of myosin in a given fiber and
the possible interconversion of fiber types in response
to experimental perturbations such as chronic use or
disuse.
Electrophoretic methods have also demonstrated
the existence of different types of myosin in skeletal
muscle (351, 352, 552, 715). With these methods five
myosin isozymes have been identified in rat muscle,
which is like the findings with immunological methods.
These isozymes result from varying combinations of
the light chains associated with the heavy chains. Of
the five isozymes of myosin, the FT extensor digitorum
longus muscle of the rat contains principally the first
four with only trace amounts of the fifth. In contrast
the ST soleus muscle contains only the fourth and
fifth isozymes. In addition to isozymes of myosin, it
has also been demonstrated that other proteins of the
myofibrillar complex exist in polymorphic forms (148-
151, 669). Table 1 summarizes the variations in the
proteins found in the contractile apparatus of skeletal
muscle. In summary there are major differences be-
tween the proteins of the myofibrils of the FT and the
ST muscles. On the basis of these differences the fibers
can be most reliably typed.
The present data suggest that under normal condi-
tions the assembly of the individual units of the myo-
fibrillar proteins occurs in such a manner that a com-
plete randomization of the subunits does not or only
rarely takes place. Thus it is unlikely that the light
chains associated with the fast-type heavy myosin will
be assembled with the slow-type myosin. The general
observation that only one class of contractile protein
is found in a single muscle fiber does not preclude the
existence of minor components of other types of pro-
teins. Examples, of this can be found in fetal and
neonatal stages (240,476,595,716,718), during chronic
electrical stimulation (437, 438, 552, 596, 715), and
after cross innervation and reinnervation (33, 421,
475). The presence of more than one form of myosin
in fetal and neonatal muscle is probably due to the
existence of polyinnervation, which disappears with
maturation (81, 82, 525-527). Fast-twitch muscle fibers
also possess a greater concentration of sarcoplasmic
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
o sedentary
2.0 trained
1.5
1.0
0.5
o 6.0 7.0 8.0 9.0 10.0
pH
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-
twitch, oxidative, glycolytic (FOG)] portions of the vastus muscle
and soleus [slow-twitch, oxidative (SO)] muscle of the sedentary
(0) and endurance-trained (e) rats. ATPase activities were deter-
mined at 25C. [From Watrus (713).]
(152), electrical stimulation (323, 325), and cross in-
nervation (157, 654).
Histochemical Differentiation of Muscle Fibers
The difference in the sensitivity of myosin for re-
taining or losing ATPase activity after exposure to
either high or low pH is a reliable method for the
histochemical classification of muscle fibers (192,533).
It is a simple, rapid, and inexpensive method for
determining the fiber composition of whole muscle or
portions of muscles. This histochemical method for
fiber identification is based on the ATPase activity
remaining in myofibrils after preincubation of serial
muscle sections at pH 10.3 results in a loss of the
histochemically demonstrable stain for myofibrillar
ATPase in fibers that have a low specific ATPase
activity of purified myosin. These fibers have ST
contractile properties. Conversely all classes of FT
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
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
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-
sistance to loss of histochemically demonstrable myo-
fibrillar ATPase at the low pH values.
In this chapter classification of skeletal muscle fibers
fibrillar ATPase (602, 642). The assumption being
made is that the acid stable and the alkaline stable
myofibrillar ATPase correspond to slow and fast con-
tractile characteristics, respectively. Justification for
using the myofibrillar ATPase staining pattern after
acid or alkaline preincubation as an indication for the
contractile properties of the fibers comes from the
finding that the ATPase activity of myosin purified
from either FT or ST muscle behaves similarly when
exposed to acid or alkaline preincubation (33). More-
over a homology exists for the reaction of antibodies
prepared from purified myosin or its subunits (includ-
ing rod, head, or light chains), with the FT or ST
fibers as identified from the histochemical methods
depending on the source of the original protein used
in antibody production (240). Hence the basic desig-
nation of the fibers is ST or FT. The FT fibers are
further subdivided into FTa , FT b , and FTc on the basis
of differences in myofibrillar ATPase stability to low
pH (see Fig. 4). The choice of the ST and FT desig-
 CHAPTER 19:
nation is not the result of any objection to the type I
and II designation. It is merely an attempt to give the
classification more physiological meaning.
This nomenclature is similar to that proposed by
Peter et al. (540) from the histochemical study of
guinea pig limb muscle. In this and most other animal
species the subgroups of FT fibers are easily discerni-
ble on the basis of large differences in metabolic pro-
files. This is most marked for the mitochondrial en-
zymes where one of the subgroups of FT fibers has a
high or higher oxidative potential than the ST fibers,
whereas another is very low in oxidative enzymes. The
FT fiber types were therefore designated fast-twitch,
oxidative, glycolytic (FOG) or fast-twitch, glycolytic
(FG). Also the designation into the basic subgroups of
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).]
FT fibers or ST fibers was based on a standard ATPase
stain (pH 10.3 preincubation) and a staining for oxi-
dative and glycolytic enzymes, and not on the basis of
ATPase staining after a combination of alkaline and
acid preincubations. In the skeletal muscle of seden-
tary man, differences in metabolic potential can be
identified from both histochemical (Fig. 4) and bio-
chemical (see Tables 2 and 4) techniques when com-
paring subgroups of FT fibers, but these are small and
an overlap is present. When subgrouping of the fiber
types in human skeletal muscle is based on ATPase
stains after both alkaline and acid preincubations
rather than stains for oxidative or glycolytic enzymes,
rather large differences are obtained in which fibers
can readily be assigned to the various groups (74-77).
560 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE
TABLE 1. Distribution of Multimolecular Forms of
Myofibrillar Proteins in Type I and Type II
Fibers of Mammalian Skeletal Muscle
Protein Type I Fiber Type II Fiber'
Myosin Slow Al homodimer Fast Al homodimer
Slow Al A2 Fast Al A2
heterodimer heterodimer
Slow A2 homodimer Fast A2 homodimer
Actin a a
Tropomyosin f3 f3
Troponin C Slow Fast
Troponin T Slow Fast
Troponin I Slow Fast
'Note that data of Gauthier and Lowey (242) suggest that
differences exist in distribution of isomeric form of myofibrillar
proteins, which could account for the presence of subpopulations of
type II fibers. [Adapted from Dhoot and Perry (151).]
Moreover this system eliminates the uncertainty that
arises when changes in the oxidative potential occur
in response to altered patterns of chronic physical
activity. Thus with extensive endurance training all
fiber types in the trained muscle may stain similarly
for oxidative capacity, thereby making identification
of fiber types based on this characteristic difficult if
not impossible. Therefore it may be wrong to include
abbreviations for the metabolic profile in the names
to identify fibers as these, at least for man, can be
misleading. The subscripts a, b, and c that we prefer
to use indicate that there are certain differences in the
populations of FT fibers. Whether they are related to
differences in the myosin isozymes, energy metabo-
lism, or other features of the muscle fiber cannot
presently be evaluated. The studies of Gauthier and
Lowey (240, 242, 243) do suggest that differences in
the isozymes of the contractile proteins exist for the
FT muscle of the rat.
Ultrastructural Basis for Skeletal Muscle
Fiber Typing
Attempts have been made to identify the fiber types
in skeletal muscle by ultrastructural features detecta-
ble by electron microscopy (238, 241, 538, 696). The
width of the Z band has been reported to vary in a
systematic manner in the different fibers of some
animals (238, 241, 696). In early studies with the rat a
fairly consistent pattern exists of a wider Z band in
the ST fibers (238, 241). In more recent studies this
relationship is less clear (239). A similar pattern has
not been demonstrated in human skeletal muscle,
however, nor has it been possible to identify the sub-
types of FT muscle based on this criterion. Sjostrom
and co-workers (643) have examined the ultrastruc-
tural features of the Z and M bands of human skeletal
muscle (Fig. 5). The fibers were identified by histo-
chemical staining for myofibrillar ATPase prior to
electron microscopy. The ST fibers had wide Z and M
bands with five strong (high-density) M-bridge lines.
The FT a fibers had Z bands of intermediate width and
three strong and two weak (low-density) M-bridge
lines. The FT b fibers had narrow Z bands and three
strong and two very weak M-bridge lines. A higher
degree of accuracy for fiber identification existed from
examination of the M rather than the Z band (95% vs.
70%). The identification of ultrastructural differences
in skeletal muscle fibers supports the concept that the
basic constitution of a fiber lies in the contractile
proteins.
Other features commonly examined with electron
microscopy are the size, shape, and concentration of
the mitochondria. Examination of mitochondria is
based on the assumption that ST muscle possesses
higher oxidative capacity and therefore a higher con-
centration of mitochondria than FT muscle. This re-
lationship between mitochondrial concentration and
contractile characteristics is not valid for FT muscles
that possess high mitochondrial concentrations (240,
540, 696). Moreover the mitochondrial content of skel-
etal muscle is markedly influenced by the amount and
type of activity of that muscle. Thus an examination
of mitochondrial features holds little promise as a
reliable method for fiber identification.
Maximal Contractile Force
Considerable interest exists in identifying the factor
or factors that contribute to the capacity of skeletal
muscle to develop tension. A plethora of reports de-
scribe muscular strength increases in response to
heavy-resistance exercise and decreases after inactiv-
ity. An interesting aspect of this topic is the question
of whether any changes occur in the contractile prop-
erties of the fibers themselves in response to different
patterns of physical activity. The central issue is
whether changes occur at the level of the individual
fiber. The capacity of a muscle or fiber to develop
force is best related to the tension produced per unit
of cross-sectional area (427). The isometric tension
developed by single, skinned, human muscle fibers in
response to ionized Ca2+ has been reported to be about
15 Nzcm" (726). Ikai and Fukunaga (381, 382) exam-
ined this relationship in man by determining both the
maximal voluntary contractile strength (MVC) and
the cross-sectional area of the arm flexor muscle in
children and adults. Cross-sectional area of the mus-
cles was estimated from ultrasound echoes; MVC was
estimated to be 6.4 kg/ern" (64 N/cm2 ) with no differ-
ences between male and female subjects.
The maximal' voluntary force as reported by Ikai
and Fukunaga (381, 382) is an overestimate of the true
capacity of human skeletal muscle. The total muscle
mass involved in elbow flexion includes the pronator
teres, extensor carpi radialis longus, and brachioradi-
alis muscles (66, 69). Moreover the placement of the
origin and insertion of the biceps brachii muscle on
the skeleton is such that in the position of elbow
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:
mechanical advantage (309, 721). On the basis of these
factors the value given by Ikai and Fukunaga can be
calculated to be about 47 Nzcm". This is similar to a
value of 40 Nzcm'' reported for the biceps brachii by
Nygaard (520) and 39 N/cm2 as determined for the
calf muscles by Haxton (314).
The cross-sectional area of the upper arm flexors
and knee extensors of man has also been estimated
from X-ray computerized tomography (100,384,578).
In two of these studies (100, 578) the fiber composition
of the muscles was estimated from biopsy samples.
This revealed that the maximal voluntary strength of
human skeletal muscle is related to fiber composition
in only a minor way. Instead total cross-sectional area
appeared to be the decisive factor.
The ability of the different types of muscle and
motor units to produce maximal tetanic tension has
been examined in the mouse, rat, and cat. Maximal
tensions ranging from 15.7 to 21.5 N/cm 2 have been
reported for the soleus muscle of the mouse (592). For
the rat soleus and extensor digitorum longus muscles
maximal tetanic tensions ranged from 19 to 21 and
from 20 to 30 N/cm2 , respectively (33, 119, 120, 122,
124). Sexton and co-workers (626, 627) reported that
there was no difference in force development between
ST and FT muscles in maximally activated, glycerol-
extracted fibers. Independent measurements of the
maximal tetanic force developed by the cat soleus and
extensor digitorum longus (215) muscles support the
concept that the intrinsic capacity of the contractile
elements to develop tension is similar for ST and FT
muscle. Burke and co-workers (97, 101), however, re-
ported the maximal tetanic tension of FT motor units
in cat muscle to be between 15 and 29 N / ern? as
compared to 6 Nzcm" for ST motor units. This differ-
ence could be due to the technical difficulties in ac-
curately assessing the cross-sectional area of the motor
units that were stimulated. If such large differences in
force-developing capacity do exist between ST and FT
motor units, its molecular basis is obscure. Differences
could exist in excitation-contraction coupling, which
ultimately involves the control of free calcium by the
sarcoplasmic reticulum. Further studies into this prob-
lem are needed. One preparation that may prove useful
for studies is the skinned muscle fiber. With this
preparation activation of the contractile process can
be initiated without involvement of the sarcolemma or
sarcoplasmic reticulum. Moreover exact assessments
of the cross-sectional area of the individual fibers can
be made so that force development per square centi-
meter is accurately determined. These data, combined
with assessments of the isozyme composition of the
fibers being tested, should clarify the issue of whether
or not intrinsic differences in the capacity to develop
tension exist between the types of muscle and whether
this is related to the polymorphic forms of myosin or
the other proteins in the contractile elements. Data
from these methods do not appear to support the
ADAPTABILITY: METABOLISM AND PERFORMANCE 563
existence of a difference in force-generating capacity
of ST and FT fibers (155).
Speed of Contraction
The speed of contraction, that is, the time to peak
isometric tension, of individual motor units has been
studied most extensively in cat and rat skeletal muscle
(33, 35, 84, 98-101, 120, 121, 217, 223, 437, 438, 489).
For the rat the mean time to peak isometric tension is
13 ms and 38 ms for the FT and ST motor units,
respectively (33, 120, 121,217,437,438). In the cat the
values for FT units in the gastrocnemius muscle range
from 32 to 43 ms (99-101). The ST motor units in the
cat soleus muscle range from 77 to 97 ms (98). In the
guinea pig these values are 82 ms for ST muscle and
21 ms for FT muscle (35).
As described earlier, a close relationship exists be-
tween the contractile speed of a muscle and the spe-
cific activity of its myosin. There is, however, consid-
erable variation around the mean value for the con-
tractile times of motor units, more than that which
could be expected from differences in the staining
intensity for myofibrillar ATPase. Differences in the
isozyme composition of myosin do exist in the different
motor units, such as between the different types of FT
fibers (239, 240, 242, 243), however, and these may
contribute to the variation in contractile speeds.
Other elements in the excitation-contraction cou-
pling system may also exert a regulatory influence on
maximal speed of contraction of the individual motor
units. Included are properties of the nerve and motor
end plate, interneuronal modulations, characteristics
of the sarcolemma and transverse-tubular system for
transmission of the neural impulse, the sarcoplasmic
reticulum and its abilty to release and sequester cal-
cium, and finally, the role of the isozymes of troponin
and tropomyosin in binding calcium and initiating
contraction. Very little is known regarding these other
regulatory factors.
Studies with man have lacked the precision for
establishing contractile properties of the individual
muscle or motor units of those from animals. In situ
stimulation of motor units has demonstrated the ex-
istence of FT and ST motor units (85, 89, 90, 94, 143-
147,237,293,294,485,600). Thus in the biceps muscle,
bimodal distributions of contraction times with maxi-
mal values of 36 ms and 90 ms were observed,
whereas in the medial head of the gastrocnemius mus-
cle the respective peak times were slightly longer.
This does not necessarily signify that differences exist
in contraction times between similar fiber types of
these two muscles since the methods for recording
tensions were different in the two studies. The longer
contraction times were observed in experiments where
the torque of the whole ankle joint was measured,
probably causing an elongation of the real time to
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
for time to peak tension was large, especially for the
faster contraction times. There are also reports of
contractile properties of biopsy samples of human
skeletal muscle (162, 163, 181, 504). These support the
existence of FT and ST motor units. The exact times
for attainment of peak tension as reported in such
studies, although they do not differ markedly from the
values cited above, are open to question since the
fibers had been cut and the integrity of the excitation-
contraction coupling system compromised. However,
membrane potential was maintained at near normal
levels in these cut but ligated muscle bundles. In these
preparations one-half relaxation times were also estab-
lished and found to be approximately four times
shorter in FT than in ST fibers (179, 504,720). When
measurements were performed in intact man, assum-
ing a selective recruitment of ST fibers at low static
contraction and that all fibers engaged in maximal
contractions only twice as fast, a relaxation rate was
estimated for the ST as compared to the FT fibers
(504).
Fatigue Characteristics
Burke and co-workers (96, 98-100, 102) have exam-
ined the response of individual motor units of cat
muscle to contractile activity (Fig. 6). In these studies
individual motor units were stimulated through the
motoneuron and the tension development and fatigue
characteristics determined. Three types of fast motor
units were discernible in the medial gastrocnemius
muscle and one slow unit in the soleus muscle of the
cat. All fast-twitch units produced high tetanic ten-
sion. One type of these fast-twitch units fatigued rap-
idly and was designated as fast twitch, easily fatigued
(FF). A second type was fatigue resistant (FR), and a
third was intermediate to the FF and FR and was
identified as F(int). All motor units of the soleus
muscle produced low tension and were resistant to
fatigue. They were designated simply as slow twitch
(S). Histochemical examination ofthe muscle revealed
that the FT and ST motor units show patterns of
staining for myofibrillar ATPase typical for the re-
spective muscles.
It has been suggested that the fast-twitch motor
unit with intermediate fatigue characteristics, F(int),
is the result of differences in the activity level of the
cats. Thus cats that were allowed freedom to exercise
had higher percentages of such motor units than cats
maintained in cages. Considerable variation existed in
fatigue properties (within each group of fibers). This
continuum of resistance to fatigue was probably asso-
ciated with the normal state of fiber use in these cats
during daily life. Resistance to fatigue was closely
related to the activities of the oxidative enzymes as
demonstrated by the staining intensity for succinate
dehydrogenase. This is similar to the findings in the
rat (176,437,441).
A similar classification of human skeletal muscle
motor units has been made (237). In these experiments
a total of 57 single motor units of the medial gastroc-
nemius muscle were activated with a bipolar stimulat-
ing electrode (Fig. 7). An electromyogram (EMG) of
a single motor unit was recorded, and tension pro-
duced by activation of a motor unit was estimated
from the torque produced in the ankle joint. As was
true for cat muscle, some motor units were more
resistant to fatigue than others. The slowest contract-
ing motor units demonstrated a small decline (2%-
20%) in twitch tension from the initial level after 3,000
stimuli delivered over a 50-min period. Two groups of
FT fibers were discernible. One had fatigue-resistance
properties similar to the ST fibers, and the other had
a reduction in tension from 50% to 75% during the
same experiment period.
Metabolic Characteristics
SUBSTRATES. Human skeletal muscle contains stores
of glycogen and lipids in addition to the more imme-
diate energy sources of ATP and creatine phosphate
(CP). A summary giving the average values for these
stores as compiled from several studies where they
were estimated from biopsy samples (see ref. 49) of
the extremity muscles is presented in Table 2.
Triglyceride content. The triglyceride content of
human skeletal muscle varies between 5 and 15 mmol/
kg wet wt (197, 198,200,203,233,234). Although these
values are from measurements made on samples of
mixed-fiber muscle freed from visible fat, the possibil-
ity remains that part of this fat is localized in the
extrafiber space. However, since bundles of fibers,
carefully liberated from freeze-dried muscle samples,
contain similar amounts of triglyceride as those given
in Table 2, the extrafiber lipid store does not appear
to have been appreciable.
The magnitude of the variation in the triglyceride
stores between various muscles of the body is un-
known. Measurements made on biopsy samples of
muscles from the leg and arm suggest that the varia-
tion is small. The localization of fat within the muscle
appears to be heterogeneous. When determinations
were made on small samples (5-10 mg wet wt) the
high values were three- to five-fold higher than the
lowest value found in 30- to 50-mg pieces of the same
muscle. Ultrastructural evaluations support the con-
cept that fat is localized in small droplets at varying
intervals in a fiber. An additional factor contributing
to the variation of the triglyceride content in skeletal
muscle is the distinct difference in the lipid content of
the individual fibers with the STfibers containing
three to five times higher levels than the FT fibers
(202). Therefore differences in the lipid content must
be expected when variation exists in the fiber compo-
sition of the tissue samples being analyzed.
Differences in the lipid content of the fiber types
can be demonstrated when sections are stained with
either Sudan black or oil red 0 (454). With these
treatments the ST fibers stain more intensely than the
FT fibers (89, 90). Since mitochondrial membrane
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
Mixed Muscle,
Substrate
umol/g wet wt
ST
Triglyceride 9.9 0.6 7.1 1.7
Glycogen 83.8 18 77.8 18
(glucose units)
ATP 5.0 0.2 4.9 0.1
CP 10.7 + 0.6 12.6 0.2
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
in the interpretation of the histochemical staining
method to estimate the triglyceride stores of the in-
dividual fibers. Consequently this method seems to
hold little promise for evaluating differences in lipid
stores of the different fiber types or in estimating
changes induced by either exercise, diet, or training.
Glycogen content. The average glycogen content
(Table 2) of human extremity muscle lies in the range
of from 50 to 90 mmol/kg wet wt. (All glycogen con-
centrations given as millimoles of glycosyl units.) Part
of this rather wide variation appears to be related
to the diet and state of physical activity of the subject
(51, 271, 373). Overall the glycogen granules are ho-
mogeneously distributed throughout the muscle fibers
with only small differences existing in the glycogen
content of ST and FT fibers or in the subgroups of FT
fibers of man (191, 201-203). Moreover only minor
variation in muscle glycogen is found when determi-
nations are made on multiple samples from the same
muscle or when assays performed on small samples
are compared with those made on larger samples from
the same muscle (373).
The glycogen content of the gastrocnemius, the
quadriceps femoris, the triceps brachii, and the biceps
brachii muscles of man all lie within the range of 50-
90 mmol/kg wet wt (373, 641). Quantitative determi-
nations of the glycogen content of the individual fiber
types present in the vastus lateralis of the quadriceps
muscle have revealed that at a glycogen concentration
of about 75 mmol/kg wet wt (:::::300 mmol/kg dry wt)
there is a 10-15 mmol/kg wet wt mean difference
between the ST and FT fibers with the latter fibers
having the higher glycogen content (201-203). It ap-
pears that for the subgroups of the FT fibers;' the FT b
fibers may contain more glycogen than the FTa fibers.
These differences in glycogen content of the muscle
fibers can be detected with periodic acid-Schiff (PAS)
stain, but at a glycogen content of 80-100 mmol/kg
wet wt or above, the staining intensity is homogeneous
and neither subjective ratings nor spectrophotometric
methods can detect differences between fibers or fiber
types (171, 559). The variation in the glycogen content
within a single fiber type has been reported to be from
about 50 to 650 mmol/kg dry wt for both the ST and
Fiber Types, JLffiol/g wet wt
FT FT.
4.2 1.2
84.7 19 83.1 18 89.2 21
5.1 0.2 5.3 0.2 4.9 0.1
14.7 1.4 14.5 1.1 14.8 1.6
FT fiber types (199, 201-203). The reason for this
variation is unknown, but it may be due in part to the
technical difficulties of separating the fiber from the
support tissue and of accurately weighing the small
tissue fragments. Thus although a close relationship
has been demonstrated between the histochemical
evaluation of the glycogen content of muscle and the
value determined biochemically, it is surprising that
these differences are not more evident in tissue stained
by standard histochemical methods.
Phosphagen. The phosphagen stores of skeletal
muscle constitute 23-25 mmol/kg wet wt with the CP
concentration being 18-20 and the ATP 4-5 mmol/kg
wet wt [Table 2; (374,418,428)]. Variations between
muscles are small. The magnitude of the variation of
these stores in the major fiber types of human muscle
has been examined (312,375). This has demonstrated
a slightly higher ATP and CP concentration in ST
fibers. These differences, however, are so small, 0.05
mmol/kg wet wt for ATP and 1-3 mmol/kg wet wt for
CP, as to be physiologically unimportant. Measure-
ments performed on samples with large differences in
fiber composition also have failed to demonstrate any
major differences in the concentrations of the high-
energy phosphates (375).
The ATP and CP concentrations in mixed-fiber
muscle of nonhuman species (primarily the rat) are
similar to those observed in human skeletal muscle
(Table 3). In spite of this, significant differences do
exist in the concentrations of ATP and CP in the slow-
and fast-twitch muscles, with the ATP content of FT
muscle being about 60% higher than that of the ST
fibers and the CP content being from 70% to 100%
higher (375).
The glycogen and triglyceride (Table 3) stores of rat
muscle and other species are generally present at lower
concentrations than that obtained in mixed muscle of
man. Thus the triglyceride and glycogen concentra-
tions of rat skeletal muscle are only 25%-33% and
33%-50%, respectively, of that found in human skeletal
muscle. For glycogen, a similar pattern of distribution
between fiber types appears to exist in most species,
with the lowest concentrations being found in the ST
muscle and only minor differences existing between
the different types of FT muscles. In contrast, the red
 CHAPTER
portion of the vastus muscle in the rat, an FT muscle,
contains the higher triglyceride content, with similar
amounts being found in the ST soleus and FT white
portion of the vastus muscle. In the guinea pig the
triglyceride content is highest in the ST soleus, lowest
in the FT oxidative red vastus, and intermediate in
the FT glycolytic white vastus (219).
ENZYME ACTIVITIES. The content and/or activities of
enzymes for contraction and energy metabolism differ
in the various fiber types of skeletal muscle. This can
be demonstrated in a variety of nonhuman species
when quantitative biochemical assays are performed
on portions of muscles or whole muscles that contain
only one fiber type (15). For man, in whom most
muscles are homogeneous mixtures of the different
types, quantitative data are more difficult to obtain,
and results at the individual fiber level are scarce. It
has been possible, with the method developed by
Essen, Saltin, et al. (203), to tease apart fragments of
single fibers from freeze-dried muscle samples and to
histochemically identify them according to type. The
remaining portion is then weighed on a quartz balance
and microchemical methods are applied.
The Ca 2+ -activated myosin ATPase determined on
pooled samples of a single fiber type was 2.5-fold
higher in the FT than ST fibers (203). The absolute
values in these studies were somewhat low due to a
loss of activity that occurred during the process of
freeze-drying and isolating the individual fibers. To
estimate the absolute values, samples containing 100%
ST fibers were obtained from soleus muscle and from
other muscles that contained increasing percentages
of FT fibers. The myosin ATPase activity of the ST
fibers averaged 0.16 {Lmol Pi-mg v-rnin", and the
value obtained by extrapolating the FT fiber content
TABLE 3. Summary of Substrate Level in Rat Heart and Various Fiber Types in Rat Muscles
Heart,
Substrate
I'mol/g wet wt
Triglyceride
Mean 1.35
Range 0.53-1.79
(231, 282, 576)
Glycogen (glucose units)
Mean 27.5
Range 24.4-31.2
(27.282,469,576,679)
ATP
Mean 4.03
Range 3.6-4.31
(375,576)*
Creatine phosphate
Mean 4.6
Range 4.1-4.9
(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.
A. Klug, and L.-J. Cartier are also included.
19: ADAPTABILITY: METABOLISM AND PERFORMANCE 567
to 100%was0.48{LmoIP j . m g - 1.min- 1 (203). This value
is only slightly less than the 0.59 {Lmol Pi-mg v-min"
reported by Barany (31) for the biceps brachii muscle,
a mixed-fiber muscle. The differences between the
activities reported in these studies appear to be the
result of a better purification of the protein by Barany
(31) made possible by the availability of a larger tissue
sample.
Some representative data about the ATPase activ-
ity of myosin prepared from both ST and FT rat
skeletal muscle are presented in Figure 8. The ATPase
activities were activated by Ca 2 +, K+, or actin. Of
these activators, actin clearly is better for differentiat-
ing the myosin from ST as compared to FT muscle.
The approximately threefold difference in the actin-
activated ATPase that exists between the myosin pre-
pared from the soleus or from white portion of the
gastrocnemius or vastus muscles corresponds closely
to the differences in the time to peak isometric tension
that have been reported for ST and FT muscle of the
rat (713). Estimations of the Michaelis constants (Km )
for the different types of myosin demonstrated that
the affinity of myosin for actin was only about one-
fourth as great for myosin from slow-twitch as com-
pared to that from fast-twitch muscles (Fig. 9).
Creatine kinase. Major differences in creatine ki-
nase activity of the fiber types appear to exist in all
skeletal muscle. For example, in human muscle the
average creatine kinase activity has been reported to
be about 222 and 333 {Lmol.mg-1.min- 1for the ST and
FT fibers, respectively (686, 689, 690). When the FT
fibers are further identified as either FTa or FT b , the
FT b fibers appear to have slightly higher activities
than the FTa fibers. In the rat the creatine kinase
activity for the FT rectus femoris muscle has been
reported to be 424 {Lmol.mg-1.min- 1 as compared to
Fiber Type, I'ffiol/g wet wt
SO FOG FG
2.13 2.45 1.95
1.35-3.10 2.02-3.08 1.52-2.45
(230-232,235,282,576)
30.3 40.8 42.6
20.7-37.8 21.7-58.2 24.8-56.1
(25,27,36,126,282,346,469,488,572,
576,577,581,608,625,676,679)
4.54 6.20 6.28
3.9-5.8 5.8-6.5 6.1-6.4
(375,576)*
11.65 16.8 18.14
9.1-12.4 13.4-18.2 16.8-20.4
(375,576)*
* Unpublished data by P. D. Gollnick, G.
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
lateralis). In an early study biopsy samples were ob-
tained from 74 male subjects from 17 to 58 yr of age,
including sedentary men and highly trained athletes
(261). For this group the average fiber composition
was 52.2% ST with a range from 13%to 98% ST fibers.
In an attempt to provide further information concern-
ing the normal fiber composition of this muscle, 69
males and 48 females (Fig. 10), all 16 yr old and
representing a random sample for this age group, were
studied (602). The mean fiber composition of the
vastus lateralis muscle for this group was 54% and 52%
 CHAPTER 19:
ST fibers for the males and females, respectively.
Within the FT fibers the FT. fibers were approxi-
mately twice as common as the FT b fibers. Similar
mean values for the percentages of ST, FT., and FT b
fibers were observed in studies of 26 men and 25
women around 25 yr of age (521). Thus ample evidence
is available to suggest that in the vastus lateralis
muscle the ST and FT fibers are about equally com-
mon, and no differences exist between the sexes.
In the studies cited above, the relative percentage
of fibers was estimated from small muscle samples
obtained with the needle biopsy (49) technique where
fragments of 200-1,000 fibers are contained in each
sample. The large variation observed in these samples
could be a reflection of a heterogeneous mixture of
fibers in the cross section ofthe vastus lateralis muscle.
The variability of the relative frequency and of the
size of the various fiber types has been examined in
whole cross sections of muscles obtained at autopsy
(173, 186, 402, 403).
A variation in the relative occurrence of the fiber
types in a muscle does not exist but it does exceed 5%-
15% when calculated for adjacent regions of the mus-
cle. A tendency for ST fibers to comprise a higher
percent of the total in the deeper parts of the muscle
is sometimes found, but this is limited and does not
exceed 5%-10%. Fiber size varies slightly in different
parts of the muscle with the ratio between ST and FT
fibers being relatively constant throughout the entire
muscle. Another approach to the study of the variation
in fiber composition and size is to take multiple biopsy
samples from the same muscle. When this was done in
the vastus lateralis muscle the coefficient of variation
for the relative occurrence of a fiber type was 5%-15%
and for the size of the corresponding type it was 5%
(261, 302, 686). A similar pattern of variation was also
found when data from 36 human muscles were ana-
lyzed (406, 407). Other studies of the vastus lateralis
muscle and the biceps brachii confirm these findings
(520).
The large range of the percentages of ST and FT
fibers observed in the population in these studies
implies that for a certain percent of the population of
males and females, their muscles are predominantly of
one or the other fiber type. This interindividual vari-
ation appears to be genetically determined because
studies with mono- and dizygotic twins have shown
almost identical fiber composition of the vastus later-
alis muscle in the monozygotic but not in the dizygotic
twins [Fig. 11; (431)].
The various muscles of the human body differ in
fiber composition. The extent of this variation is illus-
trated by data from an autopsy study where the same
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
muscle disease, are given in Figure 12B. It is apparent
that some similarities exist among muscles from the
same person. It is also apparent that although most
muscles have a mean fiber composition of about 50%
ADAPTABILITY: METABOLISM AND PERFORMANCE 573
ST fibers, some muscles, like the soleus and triceps
brachii, have a predominance of either ST or FT
fibers. In man the respiratory and trunk muscles have
mixed ST and FT fibers. The diaphragm and intercos-
tal muscles of man contain approximately equal per-
centages of ST and FT fibers (311). Muscles around
the spine appear to contain nearly 50% ST fibers but
a fairly wide interindividual variation as is seen in the
muscles of the extremities. In addition to the results
from autopsy studies, data are available from studies
where several muscles in the same subjects were biop-
sied and the fiber composition estimated (Fig. 12A).
In all important aspects these findings are analogous
to the autopsy study.
An important question is whether small muscle
samples from a human muscle, such as those obtained
with a biopsy technique (49), will give acceptable
information about the fiber composition, fiber size, or
chemical composition of the entire muscle (160, 180,
181,520,563). Repeated sampling from the same mus-
cles gives a coefficient of variation of 5%-10% for fiber
composition and size (SD in percent of the mean fiber
size or fiber composition). Large samples do not reduce
this variation substantially nor does an open versus
needle biopsy produce a significant difference (186,
261). The problem of a differential distribution of
fibers in the central as compared to the superficial
part of a muscle can be accommodated by a greater
precision in the sampling site (186). We may justifiably
conclude that for most cases the mean value for a
group of subjects closely reflects the true value for a
given muscle. However, there are instances where
considerable deviation from the mean value may occur
(186, 644); for these more reliable informaton can be
obtained from multiple biopsies taken from different
sites. This is especially true for the assessment of the
percent fiber composition.
Similar problems may also be encountered in the
determination of substrate concentrations and enzyme
activities where these are distinctly different for the
different fiber types. This problem can only be ade-
quately resolved by analysis of individual fibers. This
problem also extends to the analysis of substrate
changes in muscle where only select motor units have
been active. Under these conditions analysis of whole
muscle samples will seriously underestimate a change
such as the depletion of glycogen or an increase in a
metabolite.
Human beings, in contrast to other species, have a
more homogeneous mixture of fibers in nearly all
muscles. Thus the higher degree of specialization, with
the result that a single fiber type is seen in a muscle or
large area in some animals, rarely occurs in man.
MOTOR- UNIT RECRUITMENT
The contractile and metabolic properties that com-
bine to produce the physiological characteristics of the
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
units, in all species, are well designed for prolonged
activity, where ATP can be produced by directing
substrate flux through the oxidative pathways of the
mitochondria. In animals other than man the FT
motor units in red muscle rely primarily on either the
terminal-oxidative process or the glycolytic pathway
(or both) for ATP production. These motor units
appear uniquely suited for joining the ST units during
prolonged activity when the intensity is relatively
high. The FT motor units in white skeletal muscle
(FT b ) appear best suited for high-intensity short-du-
ration activity, where a glycolytic degradation of gly-
cogen to lactate is the primary method for ATP pro-
duction.
Some differences exist in the properties of FT motor
units contained in human skeletal muscle as compared
with those of other animals, which may result in
slightly different patterns of use for these motor units
during locomotion. First, the capacity of the ST fibers
to develop force per unit of cross-sectional area does
not appear to be significantly different from that of
FT fibers. This would reduce the need for an early
recruitment of the FT motor units when additional
tension development is required. Second, the oxidative
potential of the FTa fibers is considerably lower than
that of the ST fibers in the muscle of sedentary man.
For most other animals the mitochondrial density of
the FTa fibers may be equal to or in some cases higher
than that of ST fibers.
The systematic use of the different motor units in
response to distinct physiological demands depends on
the existence of an orderly procedure for their recruit-
ment by the central nervous system. This system is
based on the existence of motoneurons of varying size,
threshold for activation, and conduction velocity.
These properties of nerves were identified by Hursh
(377) and Rushton (597). Their importance in the
control of motor recruitment was elaborated by
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
(270). The latter circumstances suggest either that the
FT fibers possess adequate mitochondrial enzymes
and receive sufficient blood flow to support the ter-
minal oxidation required for the levels of tension they
produce during such exercise or that the lactate pro-
duced is taken up and oxidized by other muscles. Such
lactate could also be cleared by the liver.
Some of the discrepancies that exist in the literature
concerning the fiber type involvement at different
exercise intensities may be attributable to the use of
different modes of exercise. For example, cycle ergom-
eters that are mechanically braked and have light
flywheels often possess little inertial momentum. Thus
for each pedal thrust a brisk contraction may be
needed to keep a steady pace. From EMG studies it is
known that the threshold for activation of a motor
unit is reduced during brisk or ballistic-type contrac-
tions (143, 146). This situation basically applies to
dynamic exercise performed by man. Motor unit in-
volvement in various gaits has been studied, e.g., in
the rat, lion, and horse (17, 19, 21, 457, 663). It is
apparent from these studies that during walking and
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
0'0 of '\102 max
and FT motor units of oxidative type (FOG) become
depleted of glycogen early in the exercise. In contrast,
the FG motor units do not become depleted of glyco-
gen in these gaits even at high speeds but only during
galloping. This is additional evidence for a basic dif-
ference between the FT motor units of man and other
animals that have been studied.
These findings do not detract from the concept of
an orderly recruitment of motor units but point to
species differences in the programming of the recruit-
ment of the fiber types. This has implications for how
they are used in various activities.
Clearly recruitment order in man may be related
either to the requirement for tension development or
to the availability of oxygen or to both. To obtain
some perspective of what fraction of the voluntary
contractile strength is used in dynamic exercise, peak
force for a pedal thrust during cycle ergometer exercise
was measured (267, 269, 349, 640). Less than 1(\% of
the MVC was used at power productions demanding
less than the subjects' V02 max. At exercise intensities
eliciting V02 max, the corresponding value ranged from
10% to 15% of MVC. These measurements take into
31 60 74 85
consideration the knee angle at which the peak force
was developed but not the speed of contraction. When
the speed of contraction was also considered, the rel-
ative values ranged from 20% to 40% of the MVC that
could be produced at the speed of contraction obtained
at 60 rpm. Thus even at exercise intensities that pro-
duce exhaustion in 4 min, less than one-half of the
strength of the muscle was utilized.
In experiments where static contractions were held
with the knee extensors at tensions representing from
10%-20% of the MVC, only ST units became glycogen
depleted (270). At higher tensions FT units also be-
came depleted of glycogen. This suggests that with
this type of muscular activity the availability of oxygen
and the development of force influenced recruitment
of FT units since blood flow in the knee extensor group
is restricted during sustained contraction above about
20% MVC (58,59,376).
The EMG recordings from single fibers support the
concept of an orderly recruitment of motor units in a
progression from ST to FT units (143-147, 279, 493,
494, 539). The observation that the individual motor
unit is activated at specific levels of tension and ceases
 CHAPTER 19:
discharging when the tension falls below this set level
points to the level of tension development as the
primary factor in controlling motor unit recruitment
(53-55). Though there is evidence for an activation of
FT motor units before or without ST units during
high-intensity exercise (293, 294, 661), the data in
support of this concept are equivocal.
There are reports using either histochemical or elec-
trophysiological techniques indicating exceptions to
the orderly treatment of motor units as described
above (294, 295, 661). The histochemical studies are
difficult to evaluate since there is a lack of definite
proof as to the ST fiber involvement. In such studies
the reduction in glycogen was too small to be evident
from histochemical staining procedures. The EMG
recordings from single ST and FT fibers in brisk
contractions or at contractions close to MVC demon-
strate that FT units may be electrically active before
ST units, but the ST fibers are not silent (143). In
voluntary efforts with simultaneous, preprogrammed
activation of neurons in the motor cortex (40, 147), it
could be anticipated that FT units of muscle would
display electrical activity prior to ST units simply
because of a difference in the conduction velocity of
the motoneurons and the number of interconnecting
neurons. The recruitment pattern might also differ in
reflex activation of motor units by input from sensory
receptors in the skin.
The specific mechanism or sensing system to which
the central nervous system responds with varying
patterns of motor unit recruitment is unknown. It is
easy to envisage a system centered around the stretch
receptors in muscle spindles or golgi organs. Informa-
tion from these receptors could signal the need for
adding or subtracting motor units from the contrac-
tion. During prolonged submaximal exercise, where it
appears that a progressive recruitment of motor units
occurs starting with ST and finally using all units
including FT units, this could occur as a result of
failure of the ST units to produce the needed tension
as their glycogen stores are depleted and their ability
to produce the ATP needed to support contraction is
diminished.
ADAPTIVE RESPONSE IN SKELETAL MUSCLE
Different types of motor units exist in skeletal mus-
cles, and they are endowed with properties that
uniquely qualify them for specific types of activity. In
addition to the differences between major types of
motor units there are also differences between motor
units that are histologically similar. Thus there is a
broad array of contractile speeds, fiber numbers, and
metabolic potentials for the motor units in a single
muscle. This section considers what effects growth
and patterns of use (either overload or inactivity) have
in establishing, maintaining, or changing the charac-
teristics of skeletal muscle. Since activation of skeletal
ADAPTABILITY: METABOLISM AND PERFORMANCE 579
muscle by electrical stimulation or by voluntary means
can produce very different mechanical and metabolic
demands on the muscle, depending on which fibers are
engaged in generating the force, this must be consid-
ered when discussing muscle adaptation. To evaluate
whether the mode of usage may elicit different adap-
tive responses, exercise is categorized as: 1) high-re-
sistance, few-repetition exercise (strength training); 2)
low-resistance, high-repetition exercise (endurance
training); or 3) varying intermediate combinations (for
example, sprint training).
Clearly the changes in skeletal muscle that accom-
pany either use or disuse as described in this chapter
involve alterations in either the rate of protein synthe-
sis or degradation. Recently attempts have been made
to investigate these changes and to determine the
mechanisms by which they are induced and controlled
(60, 62, 244-246, 313, 332, 339, 350, 393, 414, 610, 618,
620, 677). This is an area for future investigation.
Muscle Size
In terms of its ability to adjust its size to physiolog-
ical demands, skeletal muscle is a very plastic tissue.
This is illustrated by the changes in weight that occur
during normal growth and development and in the
adult or growing animal in response to alterations in
activity patterns. Since skeletal muscle consists of
about 85% (by weight) fibers and 15% extrafiber ma-
terial (224, 348,429,447,458), a change in total weight
is a simple, yet reliable, method for estimating changes
in the fiber component of muscle. Exceptions to this
are instances where experimental perturbations or
pathological changes produce modifications in the wa-
ter and collagen content of muscle (16, 378). The
growth potential of skeletal muscle can be illustrated
in inbred animal strains such as the rat or chicken. For
the rat, the limb muscles increase about 28-fold from
fetal stage to 80 days (190) and 9- to 21-fold in weight
from the 16th to the 86th day after birth (191). For
the chicken, the weights of the gastrocnemius and
pectoralis muscle increase 40- to 90- and 300- to 600-
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
(745). Human skeletal muscles possess a growth char-
acteristic similar to that of other animals. This is
illustrated by the increase in weight of the biceps
brachii from about 2.0 g at birth to 110-150 g in the
adult (B. Saltin, E. Nygaard, and A.-S. Colling-Saltin,
unpublished observations). In addition to illustrating
the great growth potential for skeletal muscle, these
data also demonstrate that the absolute increase in
the size of muscle depends on its function as deter-
mined by its location on the skeleton.
With changes in muscle size HS a result of growth
and maturity there are also changes in the chemical
composition of muscle of the fetus as compared to that
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
78.5% water with only minor changes occurring there-
after until attaining the adult value of about 76%
water. There are also major changes in the protein
fractions of muscle (Fig. 14). This is exemplified by a
2.8-fold increase in total protein from the 14th wk of
gestation to the adult human being. Of the various
protein fractions, the biggest increase occurs in the
fibrillar fraction, which increases 3.5-fold. There are
also changes in the intracellular ion concentration
from fetal life to maturity (Fig. 15).
POSTNATAL DEVELOPMENT. Nonhuman species.
There has been considerable interest in the question
of the relative importance of changes in the size (cross-
sectional area or diameter) and number of fibers in
animal muscle. This has been an active area of re-
search for those interested in meat production. As a
result, data are available on the size and in some cases
the number of fibers in the muscle of the chicken, pig,
sheep, rabbit, and steer (114, 219, 343, 410, 487, 490,
564, 585, 645, 660). The general conclusion from these
0/0
100
90
80
70
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
opment. [Adapted from Dickerson and Widdowson (153).] 140
studies is that there is a large increase in fiber size
during normal growth and development. An example
of such data is the report that the fiber diameter of
the pig increased from an average of about 7 /lm at
birth to over 70 /lm in the adult (660). This lO-fold
change in diameter would be equal to about a 100-fold
increase in cross-sectional area if one were to assume
that the fiber areas were geometrically similar (which
they are not). Other factors that influenced the mag-
nitude of the fiber enlargement were the strain of the
animals and their state of nutrition. The lack of any
change in fiber number extended to instances where
the total muscle weight had increased more than 600
times during the growth period (507).
The number of fibers in the limb muscles of the rat
has been reported to be essentially unchanged over
the period from 4-6 days postpartum to 300 days (190,
191). The average fiber weight in the neonatal rat has
been estimated to be slightly over 2 /lg as compared to
22.4 /lg/fiber in the biceps brachii and 63.1 /lg/fiber in
the gastrocnemius muscle in the adult animal (191).
The relative increase in weight per fiber exceeds that
Water
Sarcoplasmic Protein
Fibrillar Protein
13-14wks 20-22wks Newborn 4-7mlh
FE TA L INFANT ADULT

200
150
100
~
<,
0-
W .. - Mg
E 50
OL.-.......- .......- " " " - - - - - ' ...........
Feta I mths Newbarn mths I yr
FIG.15. Intracellular ion concentrations for human skeletal mus-
cle from fetal life to adulthood. The data points marked (') are
averages of samples collected from the triceps brachii, vastus later-
alis, and soleus of 6 male and 6 female adults. [Data from Dickerson
and Widdowson (153), except those marked (') from Sjegaard (641).]
of the overall gain in weight during postnatal skeletal
muscle growth.
In contrast to the above, there are reports of in-
creases in the number of fibers in skeletal muscle of
the rat during the period from birth to 3 wk of age (72,
114,571) and in the muscles of an Australian marsupial
(71). Conversely, decreases in the fiber number of the
dog, guinea pig, and rat have been reported with age
(213, 214, 380, 571).
Man. Aherne et al. (2) examined changes in the
fibers of the deltoid, biceps brachii, rectus femoris, and
gastrocnemius muscle of man in the age range of from
37 wk of gestation to 18 yr of age. This material was
from 22 individuals, 14 males. Only rarely was there
more than one sample for a given age and not all years
were represented. In this sample the fibers in the
muscles at 37 wk of gestation ranged from 36.5 to 48.2
2
}lm with the smallest fibers in the rectus femoris and
the largest in the gastrocnemius muscles. Over the
entire age range examined, there was a nearly linear
increase in the cross-sectional area of the muscle fibers
as a function of body dimension (Fig. 16A, B). Unfor-
tunately, the fibers were not subdivided into the dif-
ferent types. In mature individuals, the average fiber
areas were approximately 2,000 }lm 2 with those in the
leg muscles being larger than those of the arm muscles.
Nevertheless during skeletal growth the longitudinal
growth of the muscle fibers is such that the average
sarcomere length in the mature muscle fibers is not
markedly different from that of the young animal (122,
252).
Colling-Saltin (123-125, 697) has examined muscu-
lar growth in the lateral portion of the quadriceps,
rectus abdominis, deltoid, biceps brachii, soleus, and
gastrocnemius muscle of 86 fetuses and 50 infants and
children to age 7. The fetal samples included material
from as early as 12-14 wk of gestation. The majority
CHAPTER 19: ADAPTABILITY: METABOLISM AND PERFORMANCE 581
of the samples were from males. The samples were
fresh frozen and stained with histochemical methods
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
'----- 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
wk of gestation and thereafter continued with differ-
- K
entiation being nearly complete at approximately 1 yr
o - Na
of age (Fig. 17). These studies revealed that at about
12 wk of gestation the average cross-sectional area was
-------.
A - P
36.3 }lm 2 This remained relatively constant until about
... 21 wk of gestation when ST fibers with an average
'------<0 0'
area of about 128 }lm2 appeared in cross sections.
Adult
These ST fibers constituted about 3% of the total fiber
population with the remainder still being small, undif-
ferentiated fibers. During the subsequent period of
gestation the percent of fibers that could be identified
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
could be typed. These fibers averaged about 200 }lm 2
in cross-sectional area. At the age of 1 yr the cross-
sectional area ofthe fibers ranged from 500 to 600 }lm 2
The cross-sectional areas reported by Colling-Saltin
are larger than those observed by Aherne et al. (2).
This difference can probably be attributed to the
different methods used to prepare the tissue.
Aherne et al. (2) used paraffin embedding as con-
trasted to the fresh-frozen tissue technique used by
Colling-Saltin (123-125). Paraffin embedding produces
a significant shrinkage of the tissue during the dehy-
dration procedure. Normally this amounts to about a
20% reduction in area. However, since the water con-
tent of fetal muscle is considerably greater (e.g., see
Muscle Size, p. 579) than that of postnatal muscle,
this could also contribute to the variability between
the fetal and mature muscles. Cross-sectional areas
ranging from about 2,500 to 10,000 }lm2 have been
observed in cryostat sections of fresh-frozen adult
human limb skeletal muscle (see Table 9). There are
a number of other studies where fiber size was deter-
mined in muscle of children and adults (67, 74, 75).
In addition to problems associated with methods of
fixation, paraffin versus fresh frozen, there are a num-
ber of difficulties associated with the assessment of
the cross-sectional area of skeletal muscle fibers (183,
326, 637, 662). First is that once removed from the
intact muscle there-is usually a shortening of the fibers
(363). In fresh-frozen sections, sarcomere length aver-
ages 2.0 }lID (range 1.8-2.2 }lm) (320, 520). This con-
trasts with 2.8 urn in the stretched state (520). Simi-
larly, Holly et al. (359) observed a 25% reduction in
the length of a muscle after removal from its skeletal
attachments. This results in an overestimate of 33% in
the fiber area. Moreover several methods can be ap-
plied in the actual determination of the area, which
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
.,.
100 tmrmnnmmTTTrmmT'i'i'n:::;:;;::;:;:;:::=:=:===~===-=----~~100
----------
Undifferentiated
12 15 20 25 30 35
Gestation
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
planimetry,2) analysis by a grid technique (or particle
size analysis), and 3) assessment of the shortest di-
ameter and estimation of cross-sectional area from the
assumption that the fibers are circular. The validity of
these methods has been discussed by Edstrom and
Torlegard (178), Aniansson et al. (11), and Song et al.
(649). Because of its ease of application one of the
most frequently used methods for estimating the cross-
sectional area of the fibers is measuring the least
diameter. The method is valid if the fiber area is
circular, which appears to be the case in fetal and
infant skeletal muscle. However, with increasing age
the fiber areas become less round and the result is a
consistent underestimate of the fiber area. This situ-
ation is illustrated in Figure 18, where it is evident
that as the fibers become larger there is a progressive
deviation from the line of identity. This method can
be used if an appropriate correction factor is employed.
Postnatal increases in muscle size are closely asso-
ciated with hypertrophy of the preexisting fibers (e.g.,
see POSTNATAL DEVELOPMENT, p. 580). Data on the
number of fibers in human skeletal muscle come pri-
marily from studies of the sartorius muscle as reported
by MacCallum (470) and Montgomery (496). Mac-
Callum made fiber counts from cross sections of five
fetuses and one full-term infant and concluded that
fiber number was established before birth. Montgom-
ery employed similar methods to estimate the total
number of fibers in the sartorius muscle from samples
including three stillborn (two fetal and one full-term)
infants, two well-nourished infants (4 and 13 mo old),
and two adults (64 and 74 yr old) of unspecified sex.
The number of fibers appearing in the cross section of
the 4-mo-old infant was about twice that observed for
the 32-wk-old fetus. There were no major differences
in total fiber number with advanced age. Histological
19: ADAPTABILITY: METABOLISM AND PERFORMANCE 583
.,.
ST
40 42 4weeks lyea r
P Age
examination of the muscle sections in the late stages
of fetal life did not reveal any evidence of mitotic
activity or of fibers undergoing "longitudinal split-
ting." On this basis Montgomery concluded that the
apparent increase in fiber number of the sartorius
muscle of man during later fetal and early postnatal
life was the result of a longitudinal fiber growth such
that more fibers appeared in the histological cross
section. The mechanisms for such a longitudinal and
circumferential growth through the addition of sarco-
meres on the distal ends of the fibers and myofibrils
has been discussed in the chapter by Goldspink in this
Handbook. The lack of increase in fiber number in the
sartorius muscle is in agreement with the observation
that there is no evidence of fiber division in the biceps
brachialis muscle of man after midgestation. Moreover
no myoblasts have been observed in the muscle of
human beings after birth, and the number of fibers in
the biceps of infants is similar to that of adults (115,
344,520).
USE AND DISUSE. Muscular strength. Heavy-resis-
tance exercise results in increases in muscle bulk in
excess of that which occurs during normal growth and
development. This is exemplified by the conspicuous
musculature of persons who engage in heavy physical
labor or in athletic events where heavy-resistance
exercise is practiced (body building). The importance
of the increase in size in response to functional over-
loads lies in the fact that the strength of a muscle is
closely related to its cross-sectional area (381, 382,
520). This principle is based on the concept that all
motor units are maximally activated during MVC (181,
643). Moreover there was little difference in the
strength per square centimeter among boys, sedentary
males, and highly trained judo athletes (381, 382). This
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
is constant. If one accepts the concept that all individ-
uals can maximally activate all motor units in a muscle
(55), it is difficult to explain the increases in force-
developing capacity that occur in the nontrained limbs
of individuals who train a contralateral limb or in
instances where the training does not produce in-
creases in the cross-sectional area of a muscle (443,
689). Such changes in the force-developing capacity
may be a function of the central nervous system rather
than of the muscle (493). Moreover isometric training
consisting of three maximal contractions sustained for
10 s and separated by 1 min of rest continued for 100
days has been reported to produce a near doubling of
the volitional strength of the forearm flexor muscles
(399). This increase occurs with only a 23% increase in
the cross-sectional area of the muscles. The non-
trained arms of these subjects increased in strength by
30% without any change in cross-sectional area of the
muscles.
Fiber cross-sectional area. There are several re-
ports in which the cross-sectional area of the fibers in
skeletal muscle of weight lifters or those who have
engaged in a variety of sports events have been ex-
amined (see Table 9). The general conclusion from
such studies has been that weight lifters generally
have larger fiber areas than sedentary individuals or
those who engage in endurance-type activities (261).
Edstrom and Ekblom (175), Costill et al. (129), and
MacDougall and co-workers (471,472) have reported
that a period of strength training results in increases
in the cross-sectional area of the FT fibers. Thorstens-
son et al. (689), however, did not observe a similar
finding in subjects who had participated in 8 wk of
 CHAPTER 19:
strength training. In the latter study this was true in
spite of an increased muscle mass and total body
potassium. Muscle mass increased by only 1 kg (2.5%),
however, which is probably too little to detect in fiber
size if the increase is not confined to only a few muscle
groups. Gollnick, Saltin, et al. (260) did observe a
selective enlargement of ST fibers after a 6-mo endur-
ance-training program. MacDougall et al. (471, 472)
have also examined the effect of weight-lifting activi-
ties on the cross-sectional area of the fibers in the
triceps muscle of man and found muscle-fiber hyper-
trophy.
Forced inactivity, for example, after injury, reduces
the cross-sectional area of the fibers in skeletal muscle
(301,471,578). Subjects whose legs are immobilized in
fixed casts as a result of radical knee surgery readily
demonstrate this phenomenon (299). In these subjects
the cross-sectional area of the fibers was similar in the
normal and the injured leg prior to surgery. After a 5-
wk immobilization there was a 27% decline in the
cross-sectional area of the ST fibers of the vastus
lateralis muscle. There was, however, no change in the
area of FT fibers. Data are also available from subjects
whose one leg had been immobilized for 15 wk as a
result of fracture (607). Such immobilizations did not
alter the composition of the muscle in terms of the
percentages of the different fiber types. However, the
cross-sectional area of both ST and FT fibers was
lower by an average of 47% and 38%, respectively. The
reduced FT fiber area after a 15-wk immobilization as
opposed to no change after a 5-wk immobilization is
probably attributable to the fact that in the latter
study the patients were encouraged to perform inten-
sive isometric contractions of the thigh. With such
contractions FT fibers are recruited, and this may be
an adequate stimulus for maintaining normal size of
the FT fibers. This was evident from the relatively
large FT fibers in these patients. When such exercise
is not performed, the FT fibers also become smaller
after a 4- to 6-wk period of inactivity induced by
putting a cast on the leg (299).
The effect of physical conditioning on the fiber size
of a normal leg and a leg after 6-8 wk of immobilization
has also been examined (301). In these experiments
computerized tomography was used to establish the
total cross section of the thigh muscles. These exper-
iments have firmly established an atrophy of the thigh
muscles as a result of chronic immobilization. This
atrophy was almost exclusively restricted to the knee
extensors, whereas the hamstring muscles were almost
unchanged (301). Moreover the relative changes in the
knee extensor cross section and fiber size were closely
correlated. A similar conclusion was reached by Ren-
strom in his study of the knee extensors in below-the-
knee amputees (578). In these investigations the total
cross-sectional area was reduced by 30% and that of
the fibers by 26%.
In animals there is also an increase in fiber area of
muscle exposed to overloads (248, 254, 255). With a
ADAPTABILITY: METABOLISM AND PERFORMANCE 585
return to normal physical activity there is a return of
fiber size to normal (255).
The nutritional status of the animal can also influ-
ence the rate and magnitude of the growth of muscle
fibers (250, 251, 309, 321, 424). In one case it was
reported that a short period of complete starvation of
young (weanling) rats resulted in an approximately
20% loss of fiber number in the skeletal muscles. In
starved and refed rats the number of fibers was normal
(321). These data are questionable, however, since the
changes reported in muscle weight, fiber diameter, and
fiber number are such that to accommodate the overall
changes there would have had to have been an elon-
gation of the fibers during starvation and a subsequent
shortening with refeeding. These data appear to be
limited by an accurate determination of total fiber
number.
HYPERTROPHY VERSUS HYPERPLASIA. There has been
considerable interest over the years in the mecha-
nism(s) by which skeletal muscles increase in size in
response to heavy-resistance exercise. The early stud-
ies of Morpurgo (500, 501) where increases in muscle
weight produced by training did not alter the number
of fibers contained in the cross section of the sartorius
muscle of the dog (one muscle having been removed
before and the other after training) have been the
cornerstone of evidence that muscular growth in re-
sponse to functional overloads occurs by hypertrophy
of the fibers and not by hyperplasia. Subsequent stud-
ies (624, 655, 685) supported this general concept.
There is also general agreement with the concept that
normal growth of muscle occurs by hypertrophy of the
fibers present in the muscle at birth.
The concept of a postnatal growth of muscle occur-
ring by a combination of longitudinal and circumfer-
ential hypertrophy of the preexisting fibers has re-
cently been challenged by reports of larger numbers
of fibers in enlarged muscle as compared to control
muscle (276,280,379,593,609,610,612,648, 704, 731).
In some cases the suggestion has been made that the
increase in fiber number was the result of new fibers
formed by a longitudinal division of preexisting fibers
(168, 303-305, 573, 593, 612, 648, 668, 701, 704, 731).
This suggestion is based in part on the observation
that fibers with points of branching or with central
cleavages exist in skeletal muscle (172, 280, 390, 573,
612, 614, 622, 668). It should be pointed out that the
existence of such fibers in skeletal muscle was reported
in 1866 by Eulenberg and Cohnheim (207) and in 1891
by Erb (194). The major impetus for espousing the
concept that increases in fiber number occur as a
result of fiber division (a so-called fiber splitting) dur-
ing muscular enlargement produced by functional
overload came from the studies of Van Linge (701)
and Reitsma (573). These investigators produced mus-
cular enlargement in the hindlimb muscles of the rat
by either denervation or surgical ablation of synergis-
tic muscles. In some cases exercise was used in com-
586 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE
bination with inactivation of a synergist to produce
further muscular enlargement. Van Linge (701) ob-
served what were considered to be new fibers in his-
tological sections of the overloaded, enlarged muscles.
These "new fibers" were described as small fibers
interspersed among normal-sized fibers. It was sug-
gested that these represented "young muscle fibers,
the growth of which was stimulated by strenuous
training." Technical difficulties were cited by Van
Linge as making it impossible to count all of the fibers
in the muscle from histological cross sections. Subse-
quently Reitsma (573) reported the existence of similar
small fibers in histological cross section of experimen-
tally enlarged muscle. Moreover when enlarged mus-
cles were digested in nitric acid and fibers teased free,
some fibers with branches and appendages of varying
length were isolated. The presence of such fibers was
interpreted as evidence that a longitudinal splitting of
the fibers was occurring. Unfortunately the total num-
ber of fibers in the muscles was not determined nor
was the frequency of the branched fibers established.
Little is known about the number of fibers in human
skeletal muscle. Etemadi and Hosseini (205) reported
that the number of fibers in the human biceps brachii
muscle was larger in an athletic subject (316,243
fibers) as compared to two sedentary individuals
(227,233 and 199,240 fibers). Ofthese subjects, the one
with well-developed musculature also had the greater
fiber diameter (45.25 /lm as compared to about 23 /lm
for the sedentary individuals). The difference in fiber
size is similar between large and small breeds of dogs
(413).
The total number of fibers in the human biceps has
been estimated from measurements of the total cross-
sectional area of the muscle determined by comput-
erized tomography and the area of the individual fibers
determined from biopsy samples (519, 521), assuming
that the majority of the fibers extend through the
whole muscle (623). In sedentary male and female
subjects the cross-sectional area of the muscle aver-
aged 11.6 em" (range: 9.8-16.1) and 8.7 em" (6.8-10.6),
respectively. These values were 12.3 em" (11.9-12.9)
and 9.0 em" (7.7-9.7) for trained male and female
swimmers. The total number of fibers in the biceps
averaged 280,000 (280,000-290,000) and 420,000
(340,000-500,000) for the sedentary female and male
subjects as compared to 320,000 (240,000-380,000) and
350,000 (280,000-400,000) for the trained female and
male subjects. These data demonstrate the existence
of considerable variation between the fiber number of
subjects and considerable overlap between the sexes
and the sedentary and trained groups. There is no
evidence of a systematic difference between the sed-
entary and the trained groups, the greater total cross-
sectional area of the muscle being attributable to the
larger cross-sectional area of the individual fibers.
A greater number of fibers in the cross section of
the anterior latissimus dorsi muscle has also been
reported for chicken where enlargement was produced
by hanging a weight on one wing (648). However, in
another study the increased cross-sectional area of the
fibers in the enlarged muscles of the shoulder of
chicken, where growth was induced by a chronic
stretch, could account for the observed greater muscle
weight (359).
Schiaffino et al. (612) surgically removed the tibialis
anterior muscle of 1- to 65-day-old rats. At time inter-
vals ranging from 4 to 76 wk postsurgery, the remain-
ing extensor digitorum longus muscles were on an
average 32% heavier, and cross sections contained 25%
more fibers than the contralateral control muscles.
The presence of fibers with branches in those teased
from nitric acid-treated muscles was used as evidence
for proliferation of fibers via splitting.
Ianuzzo, Gollnick, et al. (379) reported the existence
of 30% more fibers in the cross sections of the plantaris
muscle of rats where a doubling of its weight was
induced by the surgical removal of the gastrocnemius
muscle. The cross-sectional areas of the major fiber
types in the muscles had increased from 30% to 60%.
In this study there was no change in the fiber number
in the soleus muscle in spite of a 45% increase in its
weight. No evidence of fiber branching was observed
from the histological observation of the sections used
to determine fiber numbers.
Gonyea and associates (276, 279, 280) trained cats
to perform a weight-lifting type of activity to produce
muscular enlargement. This experimental procedure
was claimed to be a more physiological method for
producing muscular growth than the denervation or
surgical removal of synergistic muscle. Differences in
weight of from 6% to 16% between the flexor carpi
radialis muscles of the control and experimental legs
were produced by this procedure. The enlarged mus-
cles were reported to contain an average of up to 20%
more muscle fibers, and the average fiber diameters
were 9%-15% larger than those of the contralateral
control muscles. Fiber number was assessed from a
histological cross section made at the point of greatest
girth of muscle belly. The identification of fibers in
serial sections with branch points was cited as evi-
dence of fiber splitting. However, there was no evi-
dence of the frequency of this phenomenon. To pro-
duce a 20% increase it would have had to occur in
every fifth fiber. Even if one accounts for the time it
takes to induce the change, split fibers would have to
occur at a very high rate.
The number of fibers in the plantaris muscle has
been reported to decline between the ages of 6 and 45
wk in sedentary but not in trained guinea pigs (213,
214). Termination of training resulted in a progressive
loss of fibers. This suggested that a normal attrition of
fibers occurs, which could be prevented by physical
activity. In a subsequent paper (481), however, a math-
ematical model, based on changes in fiber angles with
growth, was described to demonstrate that the deter-
mination of fiber number from counts made of histo-
logical cross sections was invalid for penniform mus-
 CHAPTER 19:
cles. On this basis it was suggested that the earlier
data were in error.
The tedious nature of isolating all of the fibers of a
muscle has deterred the application of this method to
the study of normal growth and development and of
hypertrophy versus hyperplasia during work-induced
muscular enlargement. Gollnick and co-workers (275)
dissected, counted, and examined each fiber over its
entire length for bifurcations. In these studies there
was no change in fiber number in enlarged as com-
pared to control skeletal muscle in the rat. Muscular
enlargement ranging from 10% to 115% was induced in
the penniform plantaris and extensor digitorum longus
and in the parallel-fibered soleus muscle by surgical
ablation of a synergist and treadmill exercise. Muscles
were examined from 4 to 40 wk after the ablation of
the synergistic muscle. Treadmill running was for 6-8
wk and was initiated at least 4 wk (18, 378) after the
surgical removal of the synergistic muscle. Although
considerable variation in the number of fibers per
muscle existed among animals, the total fiber number
in the same muscle from the right and left leg was
similar regardless of whether it was normal or enlarged
(Fig. 19). It should be pointed out that considerable
variation exists among animals for the total number
of fibers for the same muscle (Fig. 20). The differences
in dry weight of individual fibers of the enlarged
muscle as compared to those from the normal muscle
demonstrated that the increase in weight was the
result of hypertrophy and not hyperplasia. The inci-
Fiber No. In
Thou.and. PLANTARIS MUSCLE
14
13
.,....
12
...J
;; II
.,
C
E
.,
~
10
Do
'"
1&1
9 seems appropriate to comment on the methodology
I ,
9 10 II 12 13 14
Control Lev
FIG. 19. Comparison of the number of fibers in a control and
enlarged plantaris muscle of the rat. Muscular enlargement was
induced either by ablation of the gastrocnemius muscle (el or a
combination of ablation of the gastrocnemius muscle and treadmill
exercise (0). [From Gollnick et al. (275).]
ADAPTABILITY: METABOLISM AND PERFORMANCE 587
dence of branched fibers was similar for normal and
enlarged muscles. However, the observation that
points of branching can occur anywhere along the
length of the fiber illustrates the technical difficulty of
using histological cross sections to evaluate its fre-
quency (275, 303-305, 573, 612). The appearance of
branched fibers in all muscles was interpreted as an
indication that these abnormal fibers are normally
present in small percentages and do not represent an
active process of a longitudinal division of fibers.
The finding of Gollnick et al. (275) supports the
older concept that the number of fibers in skeletal
muscle is established early in life (188, 470, 496, 624,
712) and that the exceptional enlargement that occurs
in response to a variety of overloads is a true hyper-
trophy. This supports the conclusion of Hall-Craggs
and co-workers (303-305) and of James (394) that if a
splitting of fibers in skeletal muscle does occur during
enlargement, it is of minimal importance in the overall
increase in muscular size. Moreover James concluded
from the changes in fiber cross-sectional area during
hypertrophy of the mouse extensor digitorum longus
muscle that a hypoplasia of fibers must have occurred
(395).
There are reports of increases in the DNA content
of skeletal muscle during normal growth and work-
induced hypertrophy (307, 368, 499). This could be
interpreted as an indication of the addition of new
fibers. However, the bulk of the increase in DNA
arises from the addition of connective tissue to support
enlarged fibers (18, 393). Part of the increase in DNA
is associated with a proliferation of the satellite cells
of muscle (3, 502, 503, 610, 611, 615, 616, 628). Some of
these are apparently incorporated into the existing
muscle fibers. This has been proposed as a mechanism
whereby the ratio of nuclear material to other cellular
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
of the synergists (225). This did completely inhibit
connective tissue proliferation: an almost complete
lack of new nuclei was observed in histological sec-
tions.
Since there has been a rather wide acceptance of
the concept that the total number of fibers in skeletal
muscle can increase with work-induced growth, it
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
of the muscle; 2) counting the fibers in a given cross-
sectional area cut and then estimating total fiber num-
ber by an extrapolation to the total area of the section;
and 3) making a cross-sectional cut, dispersing the
fibers in saline, and counting the fragments with an
electronic device (684). All methods appear valid for
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
that all of the fibers in a muscle are either contained
in the cross section or that changes in the number of
fibers contained in the single section are representa-
tive of any change in the entire muscle. These as-
sumptions appear to be tenable only when the fibers
lie parallel to the long axis of the muscle and traverse
the point where the cross section is made. This, how-
ever, is not the case for muscles where the fiber
arrangement is penniform. The problem with deter-
mining the total fiber number in muscles with pennate
fiber arrangement has been discussed by Clark (117)
and alluded to by others (478,490,571,704). In muscles
with a single pennate fiber arrangement all fibers could
be included in carefully spaced, multiple cross-sec-
tional cuts. With multipennate fiber arrangements the
problem is greatly compounded. It cannot be assumed
that a cross-sectional cut made through the same point
of the muscle, for example, the point of greatest girth,
includes the same number of fibers of a normal versus
an enlarged muscle since this depends on the angle
that the fibers form with the longitudinal axis of the
muscle (275). This fiber angle is known to change
during muscular enlargement (57, 309, 490). A change
in fiber angle in the mature animal is necessary to
accommodate the larger fiber diameter without any
change in the total length of the muscle. Since in-
creases in fiber number with work-induced growth
have been reported primarily for muscle with penni-
form fiber arrangements where fiber number was de-
termined from histological cross sections, these data
are open to doubt. Also the estimation of the size of
the fibers depends on the ability to section the muscle
perpendicular to the long axis of the fibers. When the
cuts are made at a tangent to the long axis of the fiber
the area and diameter will be overestimated.
The difficulty in determining the fiber number in a
muscle with a multipennate fiber arrangement is illus-
trated from the studies of Gollnick and associates
(275) and of Gonyea et al. (276, 280). Gonyea et al.
reported that the flexor carpi radialis muscle of the cat
contained about 7,500 fibers as estimated from a cross
section made at the point of greatest girth. When this
muscle was treated in a manner that permitted isola-
tion of each fiber it was found to contain about 28,000
fibers (275). Similarly, Schiaffino et al. (612) estimated
the number of fibers from cross sections of the extensor
digitorum longus to be about 3,400. When counted
directly this muscle, with a single pennate fiber ar-
rangement, was found to contain about 5,200 fibers.
SUMMARY. From birth to full maturity there is an
increase in muscle weight of from 100- to 200-fold in
the skeletal muscle of most mammals. This increased
muscle size is the result of a longitudinal growth
produced by the addition of sarcomeres to the ends of
the existing muscle fibers and by circumferential
growth produced by the addition of myofibrils. During
 CHAPTER 19:
the growth process the total number of nuclei in-
creases such that the ratio between cellular material
and nuclei remains rather constant. With added phys-
ical demands, such as heavy manual labor or weight
lifting, there is an additional increase in muscle mass.
This increased muscle mass is produced by further
increases in total cross-sectional area of the individual
fibers and not by the addition of more muscle fibers.
With disuse or with inadequate nutrition there is a
loss of muscle mass as a result of a decrease in cross-
sectional area.
Metabolic Capacity
POSTNATAL DEVELOPMENT. The skeletal muscle ofthe
newborn contains substrate concentrations and en-
zyme activities that are only slightly below those found
in later life when these are expressed per unit dry
weight (124). This could be interpreted as indicating
that parallel increases occur in all muscular compo-
nents with postnatal maturation. However, with
growth there is a continued differentiation of the fiber
types that necessitates a preferential synthesis of
either mitochondrial, cytoplasmic, or myofibrillar
proteins depending on the type of fiber that develops.
This is illustrated by the observation that at birth
histochemical staining for NADH-tetrazolium re-
ductase and a-glycerophosphate dehydrogenase
(aGPDH) does not discriminate between fiber types
(714). In the skeletal muscle of adults these histochem-
ical procedures identify major differences in the met-
abolic profiles of the fibers (35, 540). Based on dry
weight measure the increase in end-terminal oxidation
enzymes of the mitochondria does not parallel that of
the contractile proteins in all fibers (627). This has
been illustrated in mixed-fiber skeletal muscle where
the checkerboard appearance of the muscle only ap-
pears with maturation (249,253,524,695). The loss of
mitochondrial density in the FT b fibers appears to be
a function of a preferential production of myofibrillar
proteins. This growth effect can be modified by en-
durance training (4).
How this differential growth is regulated is un-
known. Since it is the rule rather than the exception,
different stimuli and regulatory mechanisms must be
present for the increases in contractile proteins and
metabolic enzymes. Evidence suggests that this is
regulated, at least in part, by the motor nerve (83,323,
334,371,465, 525-527, 544, 551, 567).
USE AND DISUSE. Phosphagen stores. There are re-
ports of increases and of no change in the ATP and
CP concentrations of human skeletal muscle with
either endurance or strength training (195, 415, 418,
472). Increases in both ATP and CP concentrations
have been reported in the limb muscles of adolescent
(195) and adult (415, 418) males after programs of
endurance training. However, when the training was
extended from 3 to 6 mo in the adult group, the ATP
and CP concentrations returned to the pretraining
ADAPTABILITY: METABOLISM AND PERFORMANCE 589
level. Only a few studies are available dealing with the
effects of immobilization or termination of training on
the phosphagen stores of muscle. Studies with animals
suggest that although there may be increases in the
phosphagen stores after training (228, 534), these mod-
ifications are small and probably biologically unim-
portant. Further proof that changes in the immedi-
ately available energy stores of ATP and CP are not
important features of adaptation to training comes
from observations of elite athletes. In these individu-
als, whether they have trained for strength develop-
ment or for endurance, the ATP and CP concentra-
tions in the muscles do not differ more than a few
moles per kilogram wet weight (-10%) from that of
sedentary individuals. Attempts have been made to
determine whether differences exist between the ST
and FT fibers (375). In these studies the ATP and CP
concentrations were found to be slightly higher in the
ST as compared to FT fibers in the muscle of female
athletes competing in endurance events (312).
Glycogen. In the first studies on the glycogen stores
of human skeletal muscle where the influence of ex-
ercise was examined, it was noted that higher values
existed in trained than in sedentary individuals (341).
Thereafter several studies, both longitudinal and
cross-sectional, demonstrated that subjects undergo-
ing strength-, sprint-, or endurance-training programs
possessed larger muscle glycogen stores (260, 373, 418,
472), although in some instances the difference be-
tween the trained and sedentary state was small. Con-
versely immobilization or detraining results in a re-
duction in the glycogen concentration of skeletal mus-
cle (299). The changes observed with activity and
inactivity are, however, well within the more dramatic
variation in the glycogen concentration of skeletal
muscle that can be induced with dietary manipulations
with or without exercise (51, 271, 396, 397, 560). The
one-leg model, that is where one leg is trained and the
other left untrained, has been useful to assess objec-
tively the quantitative effect of exercise, divorced from
either dietary or hormonal influences, on muscle gly-
cogen stores. At least three (333, 559, 603) such studies
are available where the vastus lateralis muscle of a
control and an endurance-trained leg was examined.
In these studies the glycogen concentration of the
trained leg was from 6 to 60 mmol/kg wet wt higher
than that of the untrained leg. An alternative approach
to this problem has been to examine the glycogen
content in the arm and leg muscles of individuals
whose training is primarily with either the arms or the
legs, for example, bicyclists, canoeists, and swimmers.
Such studies have revealed that the muscle glycogen
content is higher in the trained than in the control
muscles with differences varying from 20 to 101 mmol/
kg wet wt. Training increases glycogen synthase activ-
ity (95, 365, 366, 497, 559, 624, 675, 682). When activi-
ties of hexokinase and glycogen synthase were also
compared in the two legs where only one leg was
trained (559), both enzymes were found to be increased
590 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE
in the trained leg with the relative increments being
about 30%-50%. The muscle glycogen concentrations
in these studies were also increased from 38 to 50
mmol/kg wet wt. These differences represented rela-
tive increases of 47%-100%.
Although results vary, endurance training appears
to increase the glycogen stores of rat skeletal muscle
(25, 268, 273, 672). The magnitude of the increases
varies from about 25% to 70%. There are, however,
reports of no difference in the glycogen concentration
of skeletal muscle of trained as compared with seden-
tary rats (674). Moreover this increase in glycogen
appears to be localized, occurring in some muscles but
not others after endurance training (25, 268, 672). This
cannot be attributed to a specific use of the gastroc-
nemius muscle since swimming results in a large re-
duction in the glycogen content of all hindlimb muscles
(572,679). Sprint training has no effect on the glycogen
concentration of any of the fiber types found in rat
hindlimb muscle (608).
Triglyceride stores. Few studies have measured the
triglyceride concentration in human skeletal muscle,
and of these, only three were longitudinal with meas-
urements made on the same subjects before and after
training (104, 333, 498). Quantitative morphometric
techniques applied to electron micrographs have dem-
onstrated that the lipid content in muscles of seden-
tary man varies between 0.1 and 0.6 vol% depending
on the muscle examined (364, 422, 423). In muscle
from trained subjects the range for the same muscles
was from 0.2-0.8 vol%. Strength and endurance train-
ing altered the triglyceride content of muscle. Morgan
et al. (497, 498) and Bylund-Fellenius et al. (104)
observed elevation in the triglyceride content of the
quadriceps muscle after endurance training. The in-
crease was about 50% from an initial value of approx-
imately 10 pmol/g wet wt. Of special interest, however,
are results from a study where subjects trained only
one leg thereby permitting comparison with the non-
trained leg to obviate the effects of diet. In this in-
stance there was no difference in triglyceride content
of the muscles of the two legs (333). Variations in the
percent of lipid in the diet is a major factor contrib-
uting to the fluctuation in the triglyceride stores of
skeletal muscle (396). Jansson and Sylven (396, 400)
found that after 5 days of consuming a fat-enriched
diet (70% fat, 5% protein, 8 rn.I/day), the triglyceride
content of the quadriceps was 22 umol/g wet wt, and
the same after consumption of a low-fat diet (10% fat,
20% protein, 8 m.L'day). The problem of whether
physical training has a significant effect on the muscle
triglyceride content can also be examined from cross-
sectional studies. When data from several studies in
which the same methods were used are pooled, there
is a slight tendency for higher muscle triglyceride
stores in the most highly trained individuals (B. Essen,
personal communication). The variation is, however,
large. Thus factors other than physical activity may
dominate in determining the triglyceride content of
skeletal muscle. There are reports of a decline in the
triglyceride content of skeletal muscle of man with
exercise (234).
The triglyceride content of both the red and white
portion of the gastrocnemius muscle of the rat has
been reported to be reduced by training (232, 235).
Data are also available, however, suggesting that en-
durance exercise does (231, 232, 282, 572, 658) and does
not alter (27, 282, 658) the triglyceride stores in the
different skeletal muscle fiber types in the rat.
Glycolytic enzymes. The number of longitudinal
training studies focusing on changes in the activities
of glycolytic enzymes in human skeletal muscle is
limited. When these studies are divided into reports
concentrating on improving strength, speed (sprint-
ing), or endurance capacity, only one, or at the most
two, reports are available in each area. Although this
is the case, the adaptive response of the glycolytic
enzymes in skeletal muscle to varying patterns of
increased use is rather clear. Training regimens de-
signed to increase maximal strength have not pro-
duced alterations in the activities of PHOS, PFK, or
LDH (129, 443). This is true both for dynamic and
static exercise. The response of muscle appears to be
related to the total duration of the exercise. Thus no
changes were noted in muscle when the resistance was
so high that the total number of repetitions to exhaus-
tion was completed in 6 s (129). When the resistance
was lowered and the exercise extended to 30 s, how-
ever, there was a 10%-20% elevation in PHOS and
PFK activities but LDH was unchanged. A high-inten-
sity endurance training did produce an increase in
PFK activity (195, 260). Hexokinase also has been
reported to be elevated with training (497).
Further information concerning the adaptive re-
sponse of the glycolytic system comes from cross-
sectional studies of athletes competing in typical
strength and sprint-type events. Shot-putters, weight
lifters, and discus throwers have PHOS, PFK, and
LDH activities well within the range of sedentary
subjects (130, 261), whereas sprinters, jumpers, and
runners (400-800 m) usually have elevated levels of
these enzymes (130).
The influence of sprint and endurance training on
total LDH activity and on the isozymes of LDH has
been examined (638, 639). Cross-sectional comparisons
were also made between weight lifters and endurance
athletes (419, 638, 683, 688, 689). Total LDH activity
was not altered by sprint training. These results and
also the report of high values in the muscles of weight
lifters (419, 638) contrast to some mentioned above. It
has been found that the muscle of sprint-trained in-
dividuals contains a relatively high percent ofLDH 4 _ 5 ,
whereas muscle from endurance-trained individuals is
especially high in LDH l _ 2 (638). Part of the explana-
tion for the differences between athletic groups may
lie in the fiber composition of the muscle. Thus it is
known that ST fibers show not only lower LDH activ-
ities but also have high percentages of LDH l _ 2 (638,
 CHAPTER 19:
683). The type and cellular location of the LDH is also
different for the fiber types and could be an important
factor in their function (210, 211, 259, 416, 542, 702).
Clearly in future studies where adaptations of LDH
are investigated, close attention must be given to the
nature of the muscle sample that is analyzed.
How varying types and intensities of physical activ-
ity influence the activities of enzymes of the Embden-
Meyerhof pathway in rat skeletal muscle has been
described in numerous reports (see ref. 265). There
appear to be two major problems with many of these
investigations: 1) the exercise used for training was
often of insufficient intensity to place significant de-
mands on this system, and 2) in many cases the
enzymes assayed were not those generally considered
to be rate limiting or regulatory. The earliest of these
used rather short periods of swimming as the mode of
exercise. The general finding was that this mild exer-
cise stress did not elicit any change in the activities of
PHOS, LDH, or aldolase (ALD) in the rat hindlimb
muscles (264, 279, 283, 316, 318, 357). An exception
was the early report of an increased LDH activity in
rat muscle after a program of swimming 1 min the first
day and increasing the duration of the swim 1 min per
day for 30 days (729, 730).
More strenuous programs of treadmill running (up
to 2 h) have been used to train rats. These have used
speeds up to 31 m/rnin and in some cases have in-
cluded periodic sprints at 42 m/rnin (353). Increases
in PFK, pyruvate kinase (PK), triosephosphatase de-
hydrogenase (TPDH), and aGPDH of the soleus mus-
cle and decreases in these enzymes as well as PHOS
have been reported in the red portion of the quadriceps
muscle after such training programs (29). The activi-
ties of these enzymes were unchanged in the white
portion of the quadriceps. In the soleus, LDH activity
was unchanged, but it was lower in both the red and
white portions of the quadriceps muscle. The effect of
sprint training on the activities of select glycolytic
enzymes has been reported (345, 608, 659). These
studies employed treadmill running with speeds up to
99 m/rnin. In one study (659) the exercise was 45-s
bouts of running-two bouts in the morning and two
in the afternoon. At the end of a 3-wk training program
the running speed was 80 m/rnin. With the exception
of an increase in TPDH in the soleus muscle, there
were no differences in PHOS, TPDH, and LDH activ-
ities in the soleus and rectus femoris muscles 24 h
after the final exercise session. In a second experiment,
training consisted of 18 alternate periods of 30 s of
exercise and 30 s of rest (608). The training program
covered 11 wk with the final running speed of 80 m/
min attained during the 11th week. Activities of
PHOS, PFK, and PK were unchanged in fast-twitch
muscle (both red and white), whereas for the slow-
twitch soleus PHOS and PK activities were higher by
70% and 35%, respectively.
An exercise program of 10 s of running (speeds up
to 99 m/rnin) with 45 s of rest between bouts has also
ADAPTABILITY: METABOLISM AND PERFORMANCE 591
been used to study high-intensity training (345). One
bout consisted of six sprints, which were repeated
eight times with 2.5-min rest periods between bouts.
An endurance program of running 12.5 min at 35 m/
min was also studied. Activities of phosphoglucomu-
tase (PGM), LDH, and phosphoglucoisomerase (PGI)
were determined in the soleus, plantaris, and white
portion of the gastrocnemius muscle after 8-16 wk of
training. Small but statistically significant reductions
in the LDH activities of the soleus and white portion
of the gastrocnemius muscles were reported after 8 wk
of sprint training.i The activity of PGI was higher in
the plantaris but lower in the white gastrocnemius
muscles, whereas LDH and PGM were both lower in
the soleus muscle after endurance training. After 16
wk of training, LDH activity was lower in the soleus
and white portion of the gastrocnemius muscle of the
endurance-trained group, whereas PGM was lower in
all muscles. In the soleus muscle of sprint-trained
animals, PGM activity was lower. Overall the magni-
tude of these changes was small but statistically sig-
nificant.
Of the enzymes normally considered glycolytic,
hexokinase activity increases with endurance and
sprint training, as observed in rats (29, 659) and guinea
pigs (38, 541). This increased activity appears to be
related to changes in oxidative capacity of the muscle
(29, 41, 137). Even in sedentary animals the highest
activities are found in the most oxidative enzymes.
Hexokinase activity is also many times lower than
that of other enzymes in the Embden-Meyerhof path-
way. It responds rapidly, increasing shortly after the
onset of training and decreasing as quickly after ter-
mination of a training program (38). Since hexokinase
is more involved with glucose transport across the cell
membrane than in glycolysis, it cannot be considered
to be a glycolytic enzyme in the traditional sense.
Modifications in its activity appear to facilitate the
uptake and oxidation of glucose from the blood.
Two points should be considered when evaluating
the results of the experiments with rats. First, was the
exercise severe enough to stress the glycolytic path-
way? Second, were the results influenced by the time
at which the tissue samples were obtained after the
final training session? In the early experiments rats
were exercised by swimming. The oxygen uptake of
the rat during swimming is about 4.6 ml.l00 g-l.
min- 1 (19, 23, 484). This corresponds to less than 50%
of V'02max for the rat (44, 78, 142, 629). This is below
the exercise intensity that usually elicits an increase
in the lactate concentration in the blood of man. The
lack of an increase in blood lactate of swimming rats
supports the contention that this is a mild metabolic
stress (257, 274). The rate of glycogen depletion and
the increase in blood lactate that occur in the rat are
functions of exercise intensity (19, 288). At running
speeds below 22 m/rnin the lactate concentration of
the blood is about 3 mM and glycogen breakdown
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
the lactate in the blood with a maximum of about 20
mM having been observed at running speeds of about
70 m/min, At this point the rate of glycogen depletion
was 20 mmol-kg v-rnin". These data support the
contention that for the high-intensity exercise used in
the sprint studies there is a significant substrate flux
via the glycolytic pathway. With regard to the time of
obtaining the tissue samples after the final exercise
session, this varies from 1 to 3 days. This is an impor-
tant consideration since the turnover rate of the gly-
colytic enzymes lies between about one-half hour and
a few days (154, 383, 544). An example of the impor-
tance of this is illustrated by the observation that a
period of prolonged exercise can increase the PFK
activity of rat skeletal muscle (61). Since rats have
usually been studied from 1 to 3 days after the last
exercise session, it is possible that the training effect
may have been totally or partially missed. Moreover
athletes are not usually studied at the point of peak
performance, and in training studies with man the
muscle samples may be obtained one to several days
after completion of the exercise. Because of these
differing experimental protocols, the true extent of the
adaptability of these enzymes in response to physical
activity may not be fully understood.
Immobilization of the leg for from 1 to 6 wk did not
produce any change in PFK activity (299). A similar
lack of change was observed with detraining (367). In
the latter study PFK activity was similar to that of
sedentary subjects in the control phase for these
groups. Inactivity produced by de nervation of rat skel-
etal muscle results in a decline in the PK, ALD, and
LDH activities of the gastrocnemius muscle (316, 350)
that is evident as early as 7 days after nerve section.
Thereafter a progressive decline in enzyme activities
occurred until 8 wk after de nervation if activities were
only 25%-38% of those of the control animals (350).
There were, however, no changes in the activities of
PK and ALD of the soleus muscle over the same
period of time, whereas LDH had declined by 57%.
There were also major histochemical changes (589).
These data support the concept that a differential
response to forced inactivity exists for the different
fiber types.
At first inspection there are conflicting reports of
the adaptive response of the glycolytic capacity of
skeletal muscle to endurance training. Several reports
show no effect, whereas others observed substantial
increases. This apparent disparity may be due, at least
in part, to variations in the training protocols em-
ployed. In studies where elevations in "\;02 max were
induced by continuous strenuous but not maximal
exercise, glycolytic enzyme activities were unaltered
(337). In contrast, in those experiments (196, 260)
where 50%-115% increases in PFK activities were ob-
served, the exercise was performed at or very close to
"\;02 max, This probably resulted in a high demand for
pyruvate formation throughout the exercise. Likewise
for sprint exercise an increased demand on glycolysis
appears to cause adaptive changes in the glycolytic
pathways. In the study where the largest increase in
PFK was observed after endurance training, histo-
chemical staining of tissue samples for aGPDH dem-
onstrated an increased staining intensity of the FT
fibers with no apparent change in the ST fibers (260).
Chronic electrical stimulation of animal muscle via
the nerve has also been shown to alter the glycolytic
capacity of skeletal muscle (323,550,553). In contrast,
quantitative biochemical methods have failed to reveal
any differences in the total PFK activity or in that of
the individual muscle fiber types after endurance
training in the rat (29, 337). Clearly further investiga-
tions regarding the adaptability of the glycolytic path-
way to varying types of training are needed.
Mitochondrial enzymes. Though it has been known
for a long time that the capacity of muscle to consume
oxygen was related to the level of activity of the citric
acid cycle and electron-transport system, studies of
adaptations in the mitochondrial enzymes of human
skeletal muscle were not undertaken until the late
1960s and early 1970s. At that time results over a
period of time from cross-sectional studies of men and
women performing physical activity of an endurance
type were published (6, 7, 10, 48, 103, 104, 130, 132,
175,195,260,261,360,364,389,398,419,422,423,529-
531, 559, 565, 566, 602-604, 639, 664, 703, 705). Cyto-
chrome oxidase (CYTOX) and SDH activities were
found to be elevated in the trained skeletal muscle.
Exercise designed to develop strength does not alter
the activities of the mitochondrial enzymes (129, 261,
471). When this type of exercise is practiced over a
long time, it leads to a disproportionate proliferation
of the contractile proteins, resulting in a dilution of
the mitochondrial concentration in the muscle fiber,
and the activities of the enzymes expressed per unit of
muscle become lower than those of muscle from sed-
entary individuals (261, 471). This situation is analo-
gous to the growth dilution that occurs during the
early development in animals (249, 253).
Sprint training, in contrast to high-resistance train-
ing, causes a definite adaptive response with signifi-
cant elevation of the mitochondrial enzymes (603).
When performed intermittently, thereby placing a se-
vere stress on oxygen utilization, isometric strength
training also induces increases in mitochondrial en-
zymes (291). Thus it appears that the concentration of
mitochondrial enzymes is increased whenever there is
a chronic demand for a high-oxygen consumption by
the muscle. In line with this is the finding that the
largest increases in these enzymes occur after typical
endurance-training programs (260,603). It appears to
make little difference whether the exercise is per-
formed intermittently or continuously, although
changes at the level of the individual fiber may be
affected (337). Other evidence for differences in the
concentration of oxidative enzymes based on the rel-
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-
zymes for end-terminal oxidation are higher in the leg
than the arm muscles in spite of a similar fiber-type
distribution (261). The muscles of the legs are presum-
ably used more in endurance activity than those of the
arms.
The time course for the change in oxidative enzyme
activities and the concomitant change in whole-body
V0 2 m a x (Fig. 21) suggests that there is a close relation-
ship of these variables over the first 3-4 wk of training
(6). Thereafter the increase in 'V0 2 m a x levels off, but
the activity of the mitochondrial enzymes continues
to rise. This disparity in the response of the V0 2 m a x
and mitochondrial enzyme activities is further illus-
trated by comparisons of endurance athletes and sed-
entary individuals. The V02 max of the athletes may be
twice that of the control subjects, whereas the activity
of the mitochondrial enzymes of the muscle is 3- to 4-
fold higher than those of the sedentary individuals
(605). As pointed out earlier, the adaptive response in
enzyme activity is local in nature. Competitive cyclists
and endurance runners have higher activity levels for
the mitochondrial enzymes in their legs than sedentary
individuals. Canoeists resemble sedentary people in
their leg muscles but have elevated enzyme concentra-
tions in arm muscles (261). Moreover training one limb
induces changes in the muscle of that limb but not in
the muscle of the contralateral untrained limb (Fig.
22).
The enzymes in the various metabolic pathways of
the muscle cell are found in a rather constant ratio
one to another (543, 546-549). The question arises as
to whether this constant proportionality is retained
when adaptations occur in response to increased mus-
cular usage. This relationship does not appear to be
disturbed in rabbit skeletal muscle in response to
either normal physical activity, inactivity, or to
chronic electrical stimulation (551, 553). Comparisons
of enzyme activities for terminal oxidation in the hind-
limb muscles of sedentary and trained rats also sup-
port this concept (142). Note, however, the finding of
a slightly smaller increase in mitochondrial protein
than that observed for the citric acid cycle or respira-
tory-chain enzymes (353-355, 495, 532). This may be
due to the fact that some mitochondrial enzymes are
unchanged with muscular usage, for example, creatine
kinase, adenylate kinase, and aGPDH (355, 532). An
alternate explanation might be that the enlargement
of the mitochondria that occurs with endurance train-
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
.,.
50
ita
C)
z V0 2 max above 70 ml.kg-I.min-
z trained with continuous exercise possessed higher
:30
~
~
III
0
Q.
I
W
a: 20
Q.
:I:
0 uals involved in a variety of sport activities (43). Those
III
10
PRE- SOH = 3.9t.1 3.8t.34.0t.3
(n=8) (n=10) (n=8)
FIG. 22. Mean change in percent of succinate dehydrogenase
(SDH) activity of vastus lateralis with different training procedures.
Note that the mean values SD for the absolute activities are
similar before the training started. N, no training; S, sprint; E,
endurance trained; *, significant difference, P < 0.05. [Adapted from
Saltin, Gollnick, et al. (603).]
smaller amounts of surface protein needed to support
the cristae. Other studies (142,422,423) do not support
this contention.
For human skeletal muscle almost all existing data
support the concept of a constant proportionality of
enzymes. Thus increases in SDH and CYTOX activi-
ties occur in concert (322,338). Thus the capacities of
the citric acid cycle and the electron-transport chain
change in parallel. Whether enzymes in the ,8-oxida-
tion pathway adapt in similar proportion is unknown.
In one of the few studies where marker enzymes for
all of the major mitochondrial pathways were fol-
lowed, CS and CYTOX increased similarly though
with a slightly different time course, but HAD was
unchanged (104). In fact a small decline was noted
after 6 mo of training. These data are in contrast to
those from a study with middle-aged men where a
similar type of training (jogging, playing basketball,
etc.) produced parallel increases in SDH, CS, and
HAD activities (43). The activity of HAD was ob-
served to be present in a constant proportion to either
SDH, CS, or CYTOX in cross-sectional studies of
endurance-trained subjects with the ratio being close
to 1.0 (0.8-1.4) (364, 398). It is, however, conceivable
that training could produce differential responses in
enzymes of ,8-oxidation as compared to the citric acid
cycle or the electron-transport chain as a function of
the type or intensity of the exercise regimen. With
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
pathway. An indication of this possibility is found in
a study of eight long-distance runners all having
I (398). Those who
HAD activities in the leg muscles than those who
trained with intermittent exercise, despite the fact
that SDH activities were identical. Additional support
for this possibility comes from sprint-training studies
where CS, SDH, and CYTOX were elevated but HAD
was unchanged (104). In concert with this are the
results from a study of sedentary subjects and individ-
persons who participated in game-type activities had
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
mitochondrial volumes increase in FT b and FTc as
well as ST fibers with physical conditioning (9, 104).
These findings are consistent with quantitative bio-
chemical assessments of the SDH activity of ST and
FT fibers after interval and continuous training that
elicited elevations in both the total body V" 02max and
the SDH activity of mixed-fiber muscle preparation of
the two groups (337, 338). The largest increases in
SDH activities of pooled samples of the ST and FT
fibers occurred after continuous or interval training,
respectively. Cross-sectional studies have demon-
strated that SDH activities of FTa and FT b fibers can
reach values as high as those of ST fibers with exten-
sive training (398). In such instances the SDH activi-
ties of FTa and FT b fibers were 4-fold higher than
those of sedentary subjects, whereas the activity of
the ST fibers was only 2.5-fold above that in the
sedentary individuals (Table 10).
TABLE 10. Succinate Dehydrogenase Activity of
Thigh Muscle Fiber Types in Response to
Conditioning and Deconditioning
Range for Muscle Fiber Types
Maximal Mixed
Condition
Oxygen Muscle
ST FT.
Uptake
ml.kg I.min I urnol-g-rnin I
Deconditioning 30-40 5.0 4.0 3.5 4.0
Sedentary 40-50 9.2 5.8 4.9 7.0
Conditioning 45-55 12.1 10.2 5.5 11.0
(months)
Endurance >70 23.2 22.1 22.0 22.5
athletes
ST, slow twitch. FT., FT h , fast-twitch fibers of the thigh muscles.
Approximate values for maximal oxygen uptake are included.
(Adapted from data in refs. 299, 337, 398, 602.)
 CHAPTER 19:
Immobilization or inactivity causes SDH activity to
fall. This is true for sedentary and well-trained sub-
jects. In sedentary subjects the largest reductions oc-
cur in the ST fibers such that the difference in SDH
activity of the various fiber types in deconditioned
muscle is small (299). This is somewhat in contrast to
the findings for the glycolytic enzymes and indicates
that physical activity regulates the level of the mito-
chondrial more than the glycolytic enzymes.
An important aspect of the detraining studies is that
rate constants for the turnover of the enzymes can be
estimated from them. Thus it has been estimated that
the half-life of cytochrome oxidase is about 8 days in
rat skeletal muscle (62, 677). Data on this subject for
man are incomplete, and an exact evaluation of the
regulation of enzyme levels is currently not available.
A single exercise bout has been shown to produce an
increase in the synthesis of components of cytochrome
c (358). Some evidence suggests that the turnover
rates are similar for the muscle of man and rat. In
studies with man, comparisons can also be made be-
tween the rate of change in V0 2max and the aerobic
capacity of the limb muscles (Fig. 21). From such
studies it is apparent that the enzyme activities decline
faster than the V02max (7,425), the former approaching
pretraining values in 2-3 wk. At this time V0 2max was
still 10% higher than the pretraining value.
Lipoprotein lipase is an enzyme located on the in-
traluminal surface of the capillaries, and it has a key
position in the utilization of plasma triglycerides by
the tissues. The enzyme is synthesized by skeletal
muscle cells and found in skeletal muscle of man (459,
460). Lipoprotein lipase activity is related to the degree
of capillarization of the skeletal muscle (461), and it
could therefore be expected that it would become
elevated when capillary density is increased with phys-
ical training. No studies are yet available on this
subject in man. It is demonstrated, however, that
prolonged exercise causes an acute pronounced en-
hancement of the lipoprotein lipase activity (462).
Variations due to the previous 24-h physical activity
level may mask any changes due to a more permanent
elevation of the physical activity level. On the other
hand it could be anticipated that along with more
capillaries there would be more binding sites for the
lipoprotein enzyme, and this would provide an expla-
nation for higher lipoprotein lipase activity after pro-
longed exercise in the trained stage.
The effect of physical activity on the oxidative ca-
pacity of skeletal muscles of animals has been exten-
sively and intensively investigated. The models used
for increasing activity have included electrical stimu-
lation (either direct or via the motor nerve), varying
durations of swimming, endurance running, sprint run-
ning, and isometric contractions. Inactivity has been
imposed on the muscles by denervation and by limb
immobilization either by the application of restrictive
casts or joint immobilization.
One of the earliest indications of an adaptive re-
sponse of the oxidative systems of skeletal muscle to
ADAPTABILITY: METABOLISM AND PERFORMANCE 595
physical activity was the report of 50%-100% increases
in SDH activity in the hindlimb muscles of the rabbit
after 20-30 min/day of direct electrical stimulation for
15 days (113). Subsequent studies where rats were
exercised with programs of swimming did not confirm
the existence of high activities for SDH or malic
dehydrogenase (283, 317, 353).
The application of methods where rats were forced
to run either on treadmills or in exercise wheels for
prolonged periods oftime (up to 2 h) at speeds between
27 and 32 m/rnin firmly established the fact that
endurance training increases the capacity of the citric
acid cycle, fat oxidation, and the electron-transport
system (26,46,62, 142,328,345,353,354,357,434,495,
678,723,732). When the exercise is sufficiently intense,
the increases in mitochondrial enzymes occur some-
what in parallel in all fiber types present in the muscles
(678). The effect is a result of an increase in mitochon-
dria (39, 266, 268, 353, 422, 505). Histochemical stain-
ing of muscles from sedentary and trained animals for
oxidative enzymes results in an increased staining
intensity. As the staining intensity of the fibers that
are normally low in mitochondrial enzymes (FT fibers)
increases, it becomes increasingly difficult to discrim-
inate between these and the normally oxidative fibers
(ST). This has lead some investigators to conclude
that endurance training produces a conversion of one
fiber type to another (39, 172,213,214,497). But since
the oxidative capacity of all fiber types increases with
the relative ratio between fiber types remaining rather
constant, this does not constitute a change in the basic
phenotype of the fibers.
Since all components of the oxidative system appear
to respond in parallel to endurance training, the result
is that the skeletal muscles of endurance-trained ani-
mals possess greater capacities for the oxidation of
pyruvate, fatty acid, and ketone bodies. Although the
majority of the work in describing the adaptive re-
sponse of skeletal muscle to endurance training has
used the rat as an experimental subject, similar re-
sponses have been reported for the guinea pig, bush-
baby, and horse (36,39,169,646,692). Similar changes
have also been observed in the rat diaphragm when
airway resistance was increased by an experimentally
imposed stenosis of the trachea (420). It should also
be noted that the metabolic potential of the neuro-
muscular junction also adapts to endurance training
(138).
Short, high-intensity exercise such as sprinting pro-
duces smaller augmentations of the oxidative path-
ways (608). Thus 11 wk of training rats with a sprint
program of alternate periods of 30 s of running and 30
s of rest with the final running speed being 80 m/rnin
did not alter SDH activity in any of the fiber types
(608). A sprint program with fewer repetitions has
been reported to increase the CS and hexokinase
activities in the rectus femoris and soleus muscles of
the rat (659). Creatine kinase was unchanged in the
rectus femoris and increased in the soleus muscle in
this experiment. Similarly 16 wk of sprint training was
596 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE
reported to increase the fumarase activity for the
soleus, the white portion of the gastrocnemius, and
the plantaris muscles of the rat (345). A training
program of isometric contractions had no effect on the
oxidative potential of rat skeletal muscle (208).
Chronic electrical stimulation of skeletal muscle via
the motor nerve produces an overall increase in the
activity of the oxidative enzymes (323, 371).
Inactivity by various experimental procedures
causes a precipitous fall in the oxidative capacity of
skeletal muscle (316, 350, 670, 671). This has been
reported to be about 70% for succinate-cytochrome c
reductase, and about 50% for CYTOX of the rat gas-
trocnemius in 21 days. Malate dehydrogenase was 40%
and 70% lower in the gastrocnemius and soleus mus-
cles, respectively, of the rat after denervation. The
overall picture for inactivity produced by de nervation
is for a major reduction in the oxidative capacity of all
types of skeletal muscle.
Immobilization of limbs has also been reported to
result in decreases in the oxidative capacity of animal
muscle (60,64,439,474,479,582). This effect, however,
is less dramatic than that occurring with denervation
and may be minimal when the enzyme activities are
expressed per unit of muscle (170). There are, however,
reports of changes in the mitochondria with reduced
capacities to oxidize glucose, pyruvate, palmitate, and
,B-hydroxybutyrate (583). The changes are more rapid
in ST than FT muscle (64). These data suggest that
qualitative and quantitative changes had occurred in
the mitochondria with immobilization.
Studies conducted with man closely parallel those
with animals for changes in the mitochondrial en-
zymes. This includes the methods for tissue analysis
and many procedures for producing increases and
decreases of physical activity. Interestingly most of
the enzyme assays were first developed with animal
models and then applied to man. Overall the responses
observed in skeletal muscle to altered physical activity
are similar for animals and man. In each group of
subjects there are certain advantages and disadvan-
tages for their use. It has been possible to use some
experimental perturbations with animals that are not
possible with man, for example, the experiments with
chronic electrical stimulation of the muscle via the
motor nerve. There is some activity in the area of
direct electrical stimulation of muscle of man via the
nerves at motor points. Such studies may apply to
rehabilitation medicine and also to athletes during
periods of injury. Conversely there are advantages in
the study of man. Foremost among these is the ability
to use specific experimental protocols that require the
cooperation of the subjects, such as the one-leg model,
and a wide variety of individuals are available who
naturally engage in physical activity or who are sed-
entary.
Contractile properties and fiber conversion. One
important question concerning the adaptability of
skeletal muscle to varying types of overload is whether
there is a change in the fiber types. As stated initially
in this chapter, skeletal muscle fibers are classified
only on the basis of their contractile properties as can
be identified from histochemical, immunological, elec-
trophoretic, or biochemical characterization of myofi-
brillar proteins. Thus a true interconversion of a fiber
is characterized by changes in contractile properties
and in the manner that a fiber is utilized during
exercise,
There is no question that under appropriate condi-
tions muscle fibers are mutable. Perhaps the first of
these situations occurs during maturation after birth.
At birth many of the skeletal muscles of the limbs of
mammals possess contractile properties similar to the
ST muscle ofthe adult (92). During the early postnatal
period some of these muscles undergo changes in their
biochemical composition such that their speed of con-
traction attains that of the adult FT muscle (157).
During this process the myosin in fetal muscle, which
is initially undifferentiated, takes on the characteris-
tics associated with the myosin of mature FT muscle
(157, 718). The relative speed with which this conver-
sion occurs is a function of the initial size of the
newborn and the rate at which a given species matures
(92,93,119,122). For example, for the rat the extensor
digitorum longus attains a contractile speed similar to
that of the mature animal by 21 days of age (157).
During this period the ATPase of actomyosin in-
creases in parallel with the time to peak tension.
Conversely the one-half relaxation time changes in
concert with the development of the Ca 2+ -sequestering
capacity of the sarcoplasmic reticulum (157).
It is also a consistent observation that the reinner-
vation of a denervated muscle with a motoneuron that
normally innervates a muscle with dissimilar contrac-
tile properties (i.e., an ST muscle with a nerve nor-
mally innervating an FT muscle or vice versa) results
in the muscle taking on the contractile and biochemi-
cal properties associated with the new nerve (33, 121,
122,151,351,421). The experimental basis ofthis cross
innervation came from the observation of Eccles and
co-workers (165-167) that the contractile properties of
a muscle were associated with the characteristic pat-
tern of the neural impulses delivered to the muscle.
For the adult cat, ST muscle is innervated by moto-
neurons that discharge tonically at low frequencies,
whereas FT muscles receive chronic impulses in a
phasic manner at higher rates (167). These data sug-
gested that the stimulation frequency of the nerve or
the release of some neurotrophic substance associated
with the pattern of nervous discharge was responsible
for determining the contractile properties of the mus-
cle or of the individual motor units. The cross-inner-
vation studies support such a contention. Chronic
electrical stimulation produced by electrodes im-
planted on the motor nerves and applying stimulation
frequencies mimicking those of the opposite nerve
produces a similar conversion of the contractile and
chemical properties of the muscles (323-325, 371, 551-
553, 568, 599, 600). These data conclusively demon-
strated that all muscle cells retain a "genetic memory"
 CHAPTER 19:
for the synthesis of all kinds of proteins associated
with the regulation of the contractile properties.
Whether the conversion of a muscle from an ST to
an FT or the reverse depends exclusively on the fre-
quency of the stimulation or on a neurotrophic sub-
stance released from the nerve independently of the
impulse frequency has been questioned. Two experi-
mental approaches have been taken to this problem.
In the first study the soleus muscle of the rat was
denervated and electrodes implanted in it. Low-fre-
quency impulses delivered at a mean of either 1 or 9
Hz did not alter the time to peak tension but at a
mean of 9 Hz the one-half relaxation time was pro-
longed (465,488). Both the time to peak tension and
one-half relaxation times were reduced when the stim-
ulation was 100 Hz for 0.01 or 1 s. At a mean stimula-
tion rate of 1 Hz, endurance was reduced. Reinnerva-
tion of the denervated muscle by nerves normally
innervating ST muscle resulted in the appearance of
the ST contractile characteristics in spite of a contin-
ued direct electrical stimulation (469). These data
demonstrate that although direct stimulation can have
a regulatory role in the contractile properties of mus-
cle, ultimately the motor nerve is dominant. These
data do not, however, answer the question of whether
this neural dominance is due to the natural impulse
traffic mediated by acetylcholine or to neurotrophic
substances. Chordotomy, which produces electrical
silence of the nerves, may give some insight into this
question. When the spinal cord is sectioned, there is a
conversion of ST to FT muscles (187). This change is
rather slow and occurs in concert with a shift of the
myosin isozymes to those of the FT muscle. When
considered in light of the results from electrical stim-
ulation applied directly to denervated muscle, these
data suggest that the prime determinant of the con-
tractile properties of muscle fibers is the electrical
activity rather than a neurotrophic factor. These stud-
ies do not rule out the existence of neurotrophic reg-
ulators, only that without normal electrical traffic over
the end-plate region they are not effective, or that
electrical traffic in the nerve is required for a normal
transport of these substances from the nerve or across
the motor end plate. The observation that there is a
conversion of ST to FT fibers after chordotomy sug-
gests that the maintenance of ST properties depends
on chronic electrical activity.
Experimental chordotomy is like spinal cord section
in man resulting from accidents. In such patients all
fibers in the paralyzed muscle stain histochemically as
FT fibers (292). Also, in hemiplegic patients there is
an increase in percentage of FT fibers in the muscles
of the affected side (444). These data illustrate the
mutability of human skeletal muscle. This is consistent
with the conversion of ST to FT fibers in the muscles
where the nerve is intact but electrically silent. These
data suggest that for the maintenance of slow-twitch
properties the nerve must be chronically active.
Although interesting and important the above ex-
perimental approaches do not answer the question of
ADAPTABILITY: METABOLISM AND PERFORMANCE 597
whether or not the fiber distribution of skeletal muscle
can be altered by an interconversion of one type to
the other as a result of some form of "normal" physical
activity. The logical conversion would be for an in-
crease in the ST fibers in response to endurance type
activity and the appearance of a greater percentage of
FT fibers for those activities where short' explosive
contractions are required. In most of the early studies
with animal species other than man the fibers were
identified simply as red or white on the basis of stain-
ing intensities for oxidative enzymes. With such meth-
ods it was reported by a number of investigators that
there was a higher percentage of red than white fibers
in the muscles of endurance-trained animals (39, 172,
213, 214). Termination of the training program re-
sulted in a return to the control situation. By some
this has been interpreted as a conversion of white to
red fibers. A similar report also exists in a longitudinal
study of the effect of training on human skeletal
muscle (497). Such an alteration in the staining inten-
sity for mitochondrial enzymes is consistent with bio-
chemical studies demonstrating that endurance train-
ing induces increases in mitochondrial protein concen-
trations and in the activities of the oxidative enzymes
associated with the mitochondria. As seen in Table 10
this increase in oxidative potential of the muscle can
occur in all types of fibers if the intensity and duration
are adequate to produce recruitment of all motor units
in the muscle. On the other hand the short, heavy-
resistance exercise of weight lifting results in a de-
crease in the oxidative potential of skeletal muscle.
This could be viewed as an increase in the white fibers.
The criterion that has been established to identify
fiber type is a difference in the myofibrillar proteins.
On this basis changes in oxidative potential do not
represent a change in fiber type.
A significant amount of data are available on the
fiber composition of muscles of athletes. The majority
of these data have come from studies that determined
the fiber composition in biopsy samples. As a result,
there is appreciable descriptive information on the
fiber distribution of several muscles from athletes
specializing in a variety of athletic events (see Table
8). In most of these studies the fiber composition has
been assessed from the histochemical identification of
fibers on the basis of the histochemical demonstration
of myofibrillar ATPase. In some instances this has
been combined with procedures that illustrate the
metabolic profiles of the fibers from histochemical
staining procedures. From cross sections the fiber com-
position of athletes has been found to fall within the
range for normal subjects (602). Since the range en-
compassed by normal subjects is rather large, this is
not surprising.
In spite of the fact that most athletic subgroups
have fiber distributions in their muscles that are
within the range of normal subjects, there are some
indications of selective fiber distributions in certain
athletic groups. Most notably, individuals who excel
in events requiring great endurance usually possess a
598 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE
predominance of ST fibers in their muscles. Con-
versely there is a tendency for a person with sprint
abilities to have slightly higher percentages of FT
fibers. In the latter case, however, the situation is less
dramatic than for endurance athletes. On this basis it
has been tempting for some to speculate that pro-
longed exposure to a given type of muscular activity
can induce a conversion of one fiber type to another.
There are, however, few longitudinal studies to sub-
stantiate this supposition. Gollnick, Saltin, and co-
workers (260) examined the fiber composition of bi-
opsy samples from the vastus lateralis muscle of six
subjects before and after a 6-mo training program
consisting of bicycle exercise. Since this type of exer-
cise depends to a large extent on the quadriceps muscle
group, this muscle should have undergone extensive
use. The oxidative potential of the muscle was doubled
at the completion of the training period, which sup-
ports this contention. The fiber composition, as deter-
mined by staining procedures to identify fibers only as
FT or ST, was not altered by the training. Since the
FT fibers were not further differentiated into the FTa,
FT b , and FTc, there was no indication of shifts in the
distribution within this fiber group. However, if a
major shift in the fibers in the two major types did
occur, it should have been detectable with the methods
that were used. Jansson et al. (399) have examined the
fiber composition in samples from the vastus lateralis
muscles of four subjects after 18 wk of endurance
training and again after an additional 11 wk oftraining
that included exercise at high relative oxygen con-
sumption. During the period of endurance training the
subjects ran an average of 110 km/wk. The second
training program included some high-intensity exer-
cise (at 90%-100% of the V02 m a x ) in conjunction with
endurance running. The average distance run per week
was 71 km. Since samples were not taken before ini-
tiation of training, no comparisons could be made
between the sedentary and endurance-trained state.
After the second training period there was a 17%
reduction in ST fibers. This was accomodated by an
increase in the FTc (type IIC) fibers. The suggestion
was made from these data that a major conversion of
fiber types could occur as a result of training. These
authors also referred to data where the percent of ST
fibers decreased from 81% to 57% in the muscle of a
well-trained cross-country skier after a 6-wk period of
limb immobilization due to an injury. This conversion
of the ST fibers to a class of FT fibers as a result of
high-intensity exercise is not in agreement with the
data of Saltin, Gollnick, et al. (603) comparing the
fiber composition of legs of subjects studied in com-
binations of no training, endurance-training, and
sprint-training practices with one leg. Henriksson et
al. (335) examined the effect of a 50-day program of
endurance training (skiing 18 mi/day) on the fiber
composition of the human triceps brachii muscle.
There was no difference in the percent of ST fibers
before and after the training. However, there was a
reduction of about 11% in the total population of FTa
and FTb fiber. This was in part compensated for by a
5% increase in the FTc fiber population. Six months
after termination of the training there were no differ-
ences in fiber distribution as compared to that at the
end of the training period.
Pette et al. (545) have observed a similar pattern of
myofibrillar proteins when comparing FTa and FT b
fibers. There is also a lack of definitive proof that
normal physical activity produces a change from a
fast- to a slow-type fiber or the reverse in animals.
Bagby, Gollnick, et al. (22) did not observe any change
in the percent distribution of the fibers of the gastroc-
nemius muscle after either an endurance- or sprint-
training program. Chronic overload, however, pro-
duced by inactivation or ablation of a synergistic mus-
cle or by chronic stretch produces an increase in the
percentage of ST fibers in rat (296, 379) and chicken
(359) skeletal muscle. Thus the potential for an inter-
conversion of fibers does exist when the stimulus is
appropriate.
In summary, it appears that training does not pro-
duce any major shifts in the population of ST and FT
fibers in skeletal muscle. Unfortunately there is cur-
rently a lack of longitudinal studies that have encom-
passed a large enough sample and included all of the
techniques that can be used to identify fiber-type
interconversion to settle this issue. The current data
suggest that it may be possible to induce some shifts
in distribution of the subgroups of the FT fibers.
Mechanical properties. There are few reports that
examined the contractile properties of enlarged skel-
etal muscle. Some of the early experiments in this field
produced a muscular enlargement by elimination of
the synergistic muscle via tenotomy. With this model
a slowing of the normally ST soleus muscle was ob-
served in both the cat (709) and rat (451). There was
also a decrement in the maximal tetanic tension per
square centimeter 6 days after the onset of the over-
load. There was no change in the contractile properties
of the FT plantaris muscle of the rat after enlargement
produced by denervation of the soleus and gastrocne-
mius muscles or by the combination of denervation of
the synergistic muscle and treadmill exercise (56, 57).
In the latter experiments the time span between im-
position of the overload and assessment of the con-
tractile properties of the enlarged muscles was 10 wk.
The muscular enlargement averaged about 35% and
was similar whether the rats were exercised or not.
The major differences between these experiments
were the choice of mus-cle studied (an ST vs. an FT
muscle) and the time span between the imposition of
the overload and assessment of the contractile prop-
erties. The latter difference may be significant since it
has been demonstrated that there is a major increase
in the water content of the overloaded muscle after
tenotomy or ablation of the synergistic muscles (378).
Thus even if the contractile properties are corrected
for such differences and expressed on a dry weight
basis, this does not preclude the possibility that in the
intact cell normal contractile activity was disrupted as
 CHAPTER 19:
a result of the superhydrated state. After 4 wk this
situation no longer exists, and the protein content and
activities of the glycolytic and oxidative pathways are
normal (18, 378).
Only a few reports are available that examined the
contractile properties of skeletal muscle fibers after
physical training. A program of sprint training was
reported to shorten the time to peak tension of the rat
soleus muscle by 14% (659). However, this program
did not alter the contractile properties of the FT rectus
femoris muscle. This could be interpreted as a specific
change to enhance running speed. In cats a weight-
lifting program that lasted from 10 to 61 wk was
reported to increase the time to peak tension for the
flexor carpi radialis and palmaris longus muscles (both
normally FT muscles) (277, 278). In neither of the
aforementioned experiments were measurements
made of the ATPase activity of myosin. In the latter
experiments there was no evidence of a change in fiber
type as demonstrated from the histochemical staining
for myofibrillar ATPase. In contrast to these obser-
vations, Buchthal and Schmalbruch (89, 90) did not
observe any differences in the contractile properties of
the biceps brachii and triceps muscle of weight lifters.
Endurance training did not alter the contractile prop-
erties of the plantaris muscle of the Galago senega-
lensis [lesser bushbaby; (169)] or of the gastrocne-
mius-plantaris muscle group of the guinea pig (37). An
exception to this general pattern of a lack of a major
change in the contractile characteristics of muscle
after training is the report of a 14% decrease in the
time to peak tension of the rat soleus after treadmill
exercise (223). An increase in myofibrillar ATPase
activity has also been reported after endurance train-
ing (28), and a decrease with overload produced by
surgical ablation of a synergistic muscle (67). The
latter change is consistent with the greater percentage
of ST fibers as identified by the histochemical method
in the enlarged plantaris after ablation of the gastroc-
nemius muscle (378).
Forced inactivity such as occurs after immobiliza-
tion of a limb has been studied from the standpoint of
its effect on the contractile properties of skeletal mus-
cle. Immobilization of the hindlimb of the Galago
senegalensis for 5 to 6 mo did not alter the contractil-
ity of the FT plantaris muscle (170). In contrast an
elongation in the contraction times for both the ST
and FT muscles of the cat hindlimb was noted after
22 wk of immobilization (127).
The general consensus from the literature appears
to be that there are no major changes in the contractile
characteristics in response to varying types of physical
training or inactivity. In cases where changes have
been reported there is a lack of an unequivocal dem-
onstration that there has been a change in the basic
type of fibers of the muscles.
REGULATION. Clearly the adaptive response of sub-
strate levels and enzyme activities that occurs in skel-
etal muscle varies as a function of the type, duration,
ADAPTABILITY: METABOLISM AND PERFORMANCE 599
and frequency of the exercise stimulus. This suggests
that specific stimuli are generated by different pat-
terns of use and that these are somehow sensed and
translated into adaptations in the muscle. Presently
very little is known concerning the nature of the
stimuli or the manner in which they are translated
into a genetic expression.
The increased tension associated with high-inten-
sity muscular contractions may be responsible for
increases in muscle mass. Such increases in muscle
size can be demonstrated with chronic stretch of either
normal or denervated muscle (206, 427, 648). This
stretching of muscle can also prevent the atrophy
associated with limb immobilization (64). The unan-
swered question is how stretch stimulus is communi-
cated as a specific chemical signal to the genes to
induce the synthesis of proteins specific for muscular
enlargement. A commonly suggested chemical mes-
senger is the level of free calcium (206). The idea is
attractive, but it has not been demonstrated that the
elevation of free calcium associated with muscular
contractions induces adaptations in these systems.
Furthermore it is difficult to imagine this applying to
growth and development as influenced by physical
activity or to weight-lifting activities as practiced by
humans. In the latter instances the actual time of the
physical activity when the muscle experiences high
tensions may be extremely brief. Under these condi-
tions it would be expected that the level of free calcium
would return to normal as it would after all types of
motor activity. Direct electrical stimulation of skeletal
muscle cell has also been reported to increase the
synthesis of myosin (70).
It has been suggested that the level of free creatine
could induce protein synthesis, based on early experi-
ments measuring the rate of actin and myosin synthe-
sis in muscle cultures from the chicken embryo (388,
389). More rigorous tests of this possibility have failed
to reproduce the initial observation (236). Since CP is
reduced in the muscle during submaximal and heavy
exercise, the release of free creatine should occur under
both conditions. But since there is no increase in total
muscle bulk with the submaximal exercise, it seems
unlikely that creatine could be a major factor control-
ling the synthesis of myofibrillar protein. Another
possibility would be that an intracellular elevation
either of specific or general amino acids induces pro-
tein synthesis. This hypothesis is related to the fact
that after exercise there is an increased entrance of
amino acids into the muscle cell (245-247). Animal
studies have also indicated that overloads produce
increases in ribonucleic acid (RNA) and RNA poly-
merase in skeletal muscle (307,586,647). Similar meas-
urements on denervated muscle also support this no-
tion (426).
The situation regarding the control mechanism for
the increases in energy-releasing enzymes is equally
unclear. Several hypotheses have been proposed. Be-
cause the activities of the enzymes for end-terminal
oxidation respond most dramatically to prolonged ac-
600 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE
tivity, it has been suggested that this is a response to
hypoxia. This assumes that the total muscle or parts
of the muscle become hypoxic during exercise. This
may be false. Low oxygen tension has been measured
in skeletal muscle at rest when the number of perfused
capillaries is lower than during activity (361, 362, 648).
In fact with exercise the variation in intracellular
muscle fiber oxygen tension is reduced and fibers with
very low values are not observed at higher exercise
rates than in resting muscle (361, 362). Moreover
hypoxia during exercise could be assumed to be accom-
panied by elevations in the lactate concentration of
both muscle and blood. Mitochondrial enzymes in-
crease in muscle in response to training regimens
where no appreciable elevation in lactate occurs in
either blood or muscle. Some support for the lack-of-
oxygen hypothesis as a stimulus for inducing increases
in oxidative enzymes comes from studies on patients
with intermittent claudication and on high-altitude
natives (9, 42, 105, 140, 580). Mitochondrial enzyme
levels, as well as mitochondrial volumes, have been
reported to be higher in the most severely affected leg
of such patients (9, 105). These values were higher
than those of control subjects. However, examination
of the rare patients with unilateral stenosis of the
arteries to the leg has failed to verify the existence of
a different level of SDH or CYTOX activities between
the normal and the affected leg (336).
The notion that high-altitude residents have higher
oxidative enzyme activities in their muscles is based
on measurements from permanent residents of the
Andes (580). When these measurements were repeated
and the work capacity of the subjects taken into
account, it was found that men native to an altitude of
3,700 m had oxidative enzyme levels similar to sea-
level residents with comparable patterns of physical
activity (604). Conversely sea-level natives who so-
journ at high altitude do not have an increase in the
activities of oxidative enzymes in the skeletal muscles
(Fig. 23). In fact if anything, there is a slight decrease.
The latter finding may be due to a reduction in activity
associated with living at high altitude. Thus the
strength of the arguments for tissue hypoxia as the
major stimulus for the adaptive response of the oxi-
dative enzymes of the mitochondria appears to be
limited. The observation that the greatest increases in
the oxidative enzymes occur with endurance-type
training, as compared to sprint and weight-lifting ac-
tivities during which hypoxia would be greatest, is also
indirect evidence against tissue hypoxia as the specific
inducer of protein synthesis. Moreover it would appear
that the FT b fibers of man and the FG fibers of animals
would function most often under conditions of low
oxygen tension either because they have a poor capil-
lary supply or because they are recruited during pe-
riods of high-intensity exercise. If hypoxia were a
stimulus for inducing the synthesis of oxidative en-
zymes, these fibers could be expected to show very
high activities, which they clearly do not.
Stimulation of the f3-receptors of the skeletal muscle
has also been suggested as a mechanism for inducing
alterations with training (313, 314). When this hypoth-
esis was tested in rats through a chronic f3-blockade
and sympathectomy, CS, CYTOX, and SDH increased
equally in the treated and untreated animals with
endurance training (339).
In the vast number of experiments varying the
electrical stimulation pattern to a muscle, distinct
adaptations are obtained related to the type of stim-
ulation. Tonic, slow-impulse traffic generates an en-
hancement of the oxidative enzymes, whereas high-
frequency, phasic stimulation does not (465). The
adaptations occur whether the stimulation is via the
nerve or directly to the denervated muscle (465). This
suggests that it is the pattern of muscular usage pro-
duced by the electrical activity that is the controlling
factor.
The findings described above lead to the general
conclusion that the stimulus for adaptive changes in
the muscle fiber is related directly to the actual use of
the fiber. This suggests that the inducers of these
modifications are local in nature and depend on the
internal conditions within the muscle fibers. Since
similar adaptations can be induced by continuous or
interval exercise, there are obviously many methods
for inducing these local changes. Presently there is no
indication as to the nature of the inducer for the
synthesis-specific proteins or how it is related to phys-
ical activity. The adaptations preclude the existence
of a general inducing factor such as a change in the
level of an unknown factor in the blood.
A number of reports have appeared in which elimi-
nation of the major hormones known to be regulators
of protein synthesis and body growth has not blocked
the adaptation in mitochondrial enzymes to chronic
exercise (266, 680, 694) or in muscle mass in response
to acute overloads (52, 244, 693). Furthermore in-
creases in RNA, amino acid uptake, and protein syn-
thesis occur in the isolated, overloaded heart (618-
622) where there is no hormonal control. Thus non-
hormonal factors must be given close examination. It
is known that synthesis of enzymes can be induced by
elevation in substrate concentrations (221). There are
a number of substrates that become elevated during
exercise including citrate, lactate, malate, and glucose
6-P0 4 (198, 200, 269). None of these has been demon-
strated to be an inducer for the synthesis of compo-
nents of the metabolic pathways. The fact that all
components of the oxidative system increase in con-
cert appears to suggest that the general flux of sub-
strates through the system may be the inducer. Fitch
and Chaikoff (221) suggested the involvement of a
concept of "throughput" since the enzyme content of
tissue appears to be directly related to the amount of
substrate conversion occurring in a given tissue. With
the elevated metabolic rates associated with exercise,
and the total substrate conversion during prolonged
endurance-type exercise, it is entirely possible that a
 CHAPTER
mmol Ci t r a t e synthase
kg" min
d.w.
60
50
40
30
Sea level High altitude Sea level
residents residents residents
~ Sea level lIITI Sedent ary
~ Altitude Physical active
substrate flux through the system could be involved
in the induction of the increased oxidative capacities
of the different fiber types. This may be important
from the standpoint of the stability of enzymes. En-
zymes are known to be more stable in the presence of
their substrates (128).
In recent years a great deal of information has been
generated concerning the adaptability of skeletal mus-
cle to a variety of patterns of use and disuse. It would
appear that there is little need for further experiments
to explore additional types and intensities of exercise
that can influence some of these well-documented
changes. Therefore more attention should be directed
toward furthering the understanding of the processes
that induce the specific synthesis of proteins and con-
trol the genetic apparatus of the cells involved.
CONNECTIVE TISSUE
The influence of altered states of physical activity
on the strength of ligaments, or in most cases the force
required to separate the bone from ligament, has been
studied in a number of species including the rat, dog,
rabbit, and primate (518,691,692,706-708). The gen-
eral conclusion from these investigations is that the
fluctuations in the strength of the bone-ligament junc-
tion parallels the state of physical activity. Moreover
early mobility promotes a more rapid return of liga-
ment strength after surgical repair. It has also been
shown that normal ligament strength did not exist 12
wk after surgical repair when 6 wk was immobilization
and 6 wk was exercise training (691). In primates
19: ADAPTABILITY: METABOLISM AND PERFORMANCE 601
HAD mmol
g"min
d.w.
FIG. 23. Mean values for 2 mitochondrial en-
zymes [citrate synthase and 3-hydroxyacyl-CoA
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 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
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
High altitude
residents
ligament strength was below normal 20 wk after re-
sumption of activity after a period of immobilization
from wearing a cast (518).
The differences in ligament strength appear to be a
function of the total amount of ligament present, that
is, the total cross-sectional area of the ligament. This
is analogous to skeletal muscle in which strength is a
function of the cross-sectional area of the muscle with
strength per unit area of muscle being rather constant.
Limited data are available that show the effects of
training on the connective tissue of skeletal muscle
and of differences between the types of skeletal mus-
cle. However, it has been demonstrated that with a
work-induced growth of muscle there is an increased
synthesis of both deoxyribonucleic acid (DNA) and
RNA in skeletal muscle (225,393) and in the myocar-
dium (491,498). The bulk ofthis DNA has been shown
to be localized in the connective tissue (225,393,491).
When DNA synthesis was inhibited, chronic overload
still produced an increase in the cross-sectional area
of the muscle fibers but without a concomitant prolif-
eration of the interfiber support structures (225). Sim-
ilarly the induction of muscular growth in the rat
plantaris muscle by sectioning of the tendon to the
gastrocnemius muscle has been reported to increase
the activity of protocollagen proline hydroxylase activ-
ity, thereby suggesting an increased synthesis of con-
nective tissue (698). Endurance training of mice
(treadmill running) has also been reported to stimulate
connective tissue synthesis in the skeletal muscle and
tendons of mice (666) and to increase the activities of
some of the enzyme for energy metabolism (322). The
602 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE
effects of an endurance-training program on the con-
nective tissue of the rat has produced less conclusive
data. Overall this resulted in little or no change in the
total collagen or the chemical composition of the col-
lagen (433). The training was rather short, however,
and did not induce the usual increase in activity of
mitochondrial enzymes. Interestingly, a greater colla-
gen content was reported in ST as compared to FT
muscle for the chicken and rat (433,446). There was
an increase in the concentration of collagen in muscle
of chicken during stretch-induced hypertrophy (446).
Only limited data are available that concern the effect
of training on the connective tissue of human skeletal
muscle. In one study (665) it was reported that an 8-
wk training program increased the activity of propyl
hydroxylase in the vastus lateralis muscle of 69-yr-old
female but not male subjects. In a population of men
ranging in age from 33 to 70 yr Suominen and Heik-
kinen (664) observed higher activities of propyl hy-
droxylase in the vastus lateralis muscle of those who
were habitually active as compared to the sedentary
individuals. Clearly this is an area where additional
data are needed.
CAPILLARIES
The capillary is the interface between the skeletal
muscle and the vascular supply that makes the ex-
change of blood-borne materials possible. Many ofthe
features of this exchange were described by Krogh
(435, 436) in his now-classic studies. Since these pi-
oneering studies there has been considerable effort
directed towards furthering the understanding of this
system. Since the functioning of skeletal muscle during
exercise depends to a large extent on the perfusion of
the muscle with blood, attention is focused here on
some of the factors that contribute to this process.
This includes a description of the number, length, and
diameter of the capillaries as they are related to and
surround the muscle fibers. Although such measures
do not give any indication of the number of open
capillaries, of blood flow either at rest or during exer-
cise, or of the permeability characteristics for the
exchange process, all of which are essential in deter-
mining the transport rate for specific substances, they
do give estimates of the upper capacity for blood flow
in the muscle. This situation is similar to the use of
maximal activity (Vmax) for enzymes as an indicator of
the potential substrate flux through a specific meta-
bolic pathway.
There has been some attention paid to the effect of
varying patterns of physical activity on the capillary
supply to muscles and of the differences in capillary
supply that may exist among the different types of
muscle fibers. Since the results of such studies may
depend on the methodology used, a brief discussion of
some of the problems associated with each method is
given. Further, a short description of the present un-
derstanding of capillary architecture is included.
Methodology
There are basically three methods that have been
used to visualize capillaries in skeletal muscle: 1) in-
jection of a dye into the capillary lumen, 2) staining
the capillary wall, and 3) vital microscopy. There are
problems associated with all three methods. Spalten-
holz (650) pioneered this work with injection of a dye
into the vascular tree. This method can give good
estimates both of number and length of capillaries. In
addition the anatomy, i.e., the structural relationship
between capillaries and muscle fibers, is seen. The
drawbacks are that not all capillaries may be filled
and that in the preparation for microscopy a profound
shrinkage occurs. The latter problem can in part be
accounted for by determination of a shrinkage factor,
but it does not account for possible distortion in the
preparative work. Various techniques have been used
to overcome the nonhomogeneous filling, but at the
present time this problem appears to be unsolved and
an underestimation in the total number of capillaries
can be the result. In preparing the tissue to identify
the muscle cells, a hematoxylin-eosin stain has been
used. In doing so the nuclei of the cell are stained
quite dark. It is possible that some of the peripherally
located nuclei have been misinterpreted as capillaries
stained with dye, resulting in an erroneously high
capillary count. This could be a likely explanation for
the extremely high capillary densities found in some
earlier studies, as first pointed out by Pappenheimer
(535).
Techniques to stain the capillaries, either the basal
membrane or the endothelial cells, have not been used
as extensively as the injection methods. These tech-
niques have the advantage that they can be combined
with staining of cross sections of the muscle so that
the fibers in the section can be identified with regard
to contractile and metabolic characteristics. Further,
these stains can be used on sections of frozen samples,
which minimize shrinkage, and the distortion may also
be at an acceptable level. The major drawback is that
only the number of capillaries in cross sections can be
counted. Further, there is a risk that not all capillaries
are stained. Alkaline phosphatase appears to be the
safest stain for capillaries, but myofibrillar ATPase
after acid preincubation also functions in many spe-
cies. However, neither of these reactions stain capil-
laries in human skeletal muscle well (5, 6). The reason
for this is obscure. The PAS reaction stains the basal
membrane of the capillaries in human muscle. If the
sections are pretreated with amylase, the capillaries
can easily be identified [Fig. 4; (5)]. The PAS stain or
electron-microscopic technique for identifying capil-
laries in human skeletal muscle gives the same number
of capillaries per fiber (520).
The vital microscopy technique gives detailed infor-
mation about the number of capillaries and their
length and diameter. The flow rate can also be esti-
mated in the various capillaries. The problem with the
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
visualize the structures can offset the normal state.
This is probably not a major problem when counting
the capillaries but the diameter of the capillary and
the flow may be affected (196, 281, 477, 483, 509).
Anatomy
The arrangement of the capillaries in skeletal mus-
cle was the focus of many of the early studies [(477,
570, 650); for further references, see ref. 370]. In sum,
in white muscle the majority of capillaries run parallel
with the muscle fibers, but there are also capillaries
that encircle the fibers. In red muscle the capillaries
have a more tortuous arrangement. They also seem to
form parallel loops. In addition several studies point
to definite widening of some capillaries in the venous
end where capillaries join the venules (for references,
see ref. 369).
In more recent studies, Eriksson and Myrhage have
worked out some of the details of the configuration of
the microvascular supply in the thin and flat tenuis-
simus muscle of the rabbit [(196); Fig. 24]. In many
essential parts their results confirm the earlier obser-
vations. Running parallel to the muscle and along its
side are the main feeding artery and a vein. From
these vessels transverse arterioles and venules branch
off at angles of 45 0 -90 0 From such a transverse arter-
iole and vein there is a mean of 10-15 branches. After
a distance of 1-2 mm the smallest arterioles subdivide
into capillaries. These run essentially parallel to the
muscle fibers. Two capillaries may join in one small
venule or end at an almost right angle in a larger
venule. The capillaries are joined at regular distances
by anastomoses. The average length of the capillary
in this muscle is 1,000 /lm with a large variation around
this mean. The average diameter is slightly smaller
than the diameter of the red blood cell of the rabbit
(5.7 vs. 5.5 urn) and somewhat wider in the venular
than the arterial side. In spite of large differences in
the size of the muscle fibers, an almost identical num-
ber of capillaries was found around each of three fiber
types (3.5 capillaries per fiber) with a mean of one
capillary per fiber giving a sharing factor of 3. With
the same technique other muscles and other species
have been studied and the same general arrangements
of the vessels have been found although the values for
number and length of the capillaries vary (477, 507,
509).
Hammersen (306) has presented evidence that the
very regular pattern for the microvascular tree ob-
served in these thin muscles studied by vital micros-
copy may not apply to all muscles. In his own studies
using an injection technique to visualize the capillaries
in various rat and rabbit muscles, the arrangement
was more complex. He found ramification to adjacent
capillary beds to be much more frequent. Further,
close to the venous end of the capillary the number of
interconnections rose considerably. Several of the cap-
illaries unite to form small venous stems. In addition,
unramified capillaries were found that ran along 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
that the concept for a "terminal vascular unit" does
not fit for skeletal muscle tissues. Basically, Myrhage
and Eriksson (507) reached the same conclusion when
extending their studies to cat gastrocnemius muscle
and with an injection technique. These more recent
studies have also brought new evidence on controver-
sial topics such as arteriovenous anastomoses and
capillary sphincters (161, 196, 361, 362, 477). In none
of the studies with vital microscopy could the presence
of arteriovenous anastomoses be verified. Besides, the
ultralong unramified capillaries described by Ham-
mersen did not function as an arteriovenous anasto-
mosis (306). The explanation offered for regulation of
flow in various capillaries is that smooth muscle cells
in the wall of the terminal arteriole surround the
capillary at the branching point and function as
"sphincters," because no precapillary sphincters can
be detected with a vital microscopy technique. How-
ever, Hammersen has pointed out that these can be
difficult to visualize with this technique (306), and the
existence of capillary sphincters remains to be proved.
Capillary Density
From the very first studies of skeletal muscle capil-
laries, the number per fiber or unit area has been
estimated. Rather complete lists can be found in re-
views by Hudlicka (369, 370). The significance of an
estimate of the number of capillaries in a muscle is
limited as long as length and diameter of the vessel
are unknown. However, capillary number in a cross
section of a muscle fiber bundle can give information
on several subjects of importance for the understand-
ing of skeletal muscle capillary physiology.
GROWTH AND DEVELOPMENT. Postnatal growth of
skeletal muscle is due to enlargement in both diameter
and length of existing muscle fibers. This means that
the capillaries surrounding the fibers are pushed apart,
and the number of capillaries per square millimeter
(density) decreases. The most detailed studies have
been in growing rats, where capillary density and
muscle fiber size in various muscles have been exam-
ined in rats weighing from 90 to over 600 g. Over this
range of weights, the number of capillaries per square
millimeter was lowered from 1,300 to 400-500 in the
gastrocnemius and soleus muscles (584, 633, 634). A
similar trend was found for the tibialis anterior muscle,
but the absolute values were higher. The number of
capillaries surrounding the fibers increases with en-
larged muscle fiber size, with a concomitant increase
in sharing factor. The reduction in capillary density is
less, however, and the increase in capillaries surround-
ing the fibers is larger than could be anticipated from
the growth of fiber size. This is due then to an increase
in capillaries per fiber found with development. In the
aforementioned muscles of the rat the number of
capillaries per fiber increased from 1 to 2 (gastrocne-
mius) and 1 to 3 (soleus) (633,634). Similar results are
available for the chicken, where the number of capil-
laries per fiber is approximately 0.5 at birth and in-
creases to 1-1.5 in the adult muscle (65).
In growing rats a very close relationship exists be-
tween body weight and muscle fiber size [r = 0.98
(633)]. Thus with enlargement of the body and a
smaller metabolic rate per weight of the animal, skel-
etal muscle capillarization also goes down. This is in
line with the old observations [for references, see
Hudlicka (369)] that small animals have a higher
capillary count than larger species. A good illustration
of this is found in the work by Schmidt-Neilsen and
Pennycuik (617). They studied the masseter muscle
from 10 species varying in weight from 9 g (bat) to
200-450 kg (pig, cattle). The number of capillaries per
fiber was surprisingly similar (1-2.5) but the number
of muscle fibers per square millimeter was around
2,000 in the bat and 500-1,000 in pigs and cattle,
resulting in over 3,000 capillaries/rnm" in the bat and
fewer than 500 in the pig.
MUSCLE FIBER TYPES AND POTENTIAL FOR OXIDATIVE
METABOLISM. Ranvier was the first to demonstrate a
difference in red and white muscles in degree of cap-
illarization (570). Since then quite a few studies have
presented evidence in support of this early finding, but
systematic studies on the subject are scarce. The
explanation is that with injection techniques it is
difficult to identify fiber types and their metabolic
potential. Romanul (588), combining a stain for alka-
line phosphatase to visualize capillaries in muscles
from the rat, rabbit, and man with stains for mito-
chondrial enzymes, has made a plea for a very
close coupling between the oxidative metabolic capac-
ity of a fiber and the number of capillaries surrounding
the fiber. Further, in studies with cross innervation of
muscles the capillary count did change in relation to
alteration in the oxidative capacity of the muscle fibers
(590). He supports his contention with excellent mi-
crographs, but no detailed mathematical treatment of
the results is presented. Ample evidence is available,
however, demonstrating differences in capillaries of
ST and FT fibers (cf. Fig. 4). This appears to be true
for both human and nonhuman species. In the medial
gastrocnemius muscle of the guinea pig and the rabbit,
the difference is not pronounced (473), but in the
lateral head of the gastrocnemius muscle and tibialis
anterior muscles of the rabbit, the difference is more
substantial (633). This is not directly apparent from
values of capillaries per square millimeter or per fiber.
The size of the various fiber types also has to be taken
into account, as ST fibers usually are smaller than FT
fibers.
Gray and Renkin (285) found in their detailed study
of muscles of the rabbit that the average capillary
density was twice as high for ST as for FT fibers. On
this particular topic a considerable amount of infor-
mation is available on human muscle, as so many of
the studies of capillaries in human muscle have utilized
 CHAPTER 19:
serial frozen sections where staining of the capillary
basement membranes was done concurrently with
evaluation of metabolic profile and muscle fiber type
(5,8,11,313,326,520,523,602). In mixed muscles such
as the gastrocnemius, the number of capillaries sur-
rounding a specific fiber type is between 3-4 for ST
fibers and 2.5-3 for FTa and 2-3 for FT b fibers, Not
until the fiber size is taken into account can a signifi-
cant difference in capillarization of the various fiber
types be established. In the untrained muscles studied
the average area a capillary supplies is 20%-30% more
for FT b and 10%-20% more for FTa than for ST fibers.
The absolute values may vary markedly between in-
dividuals and also between muscles but the overall
pattern is remarkably stable. What contributes to this
rather small difference is the fact that in large parts of
mixed muscle, FT fibers share capillaries with adjacent
ST fibers. In locally homogeneous areas of mixed
muscle where an individual muscle fiber is surrounded
only by those of similar type, it was found that there
are 1-4 capillaries per FT fiber but 4-11 capillaries per
ST fiber (G. Sjegaard, personal communication). Ac-
counting for differences in fiber size, the ratio for the
fiber-type area each capillary had to supply could be
estimated to be in the order of 3:1 for ST and FT
fibers, respectively. The value found in human muscle
is not much different from similar calculations made
by Renkin and co-workers (285, 575) on rabbit muscle.
It must be reiterated, however, that such extreme
differences are rarely seen in human muscles since
especially FT (FT b ) fibers are seldom surrounded only
by fibers of the same type.
The concept of a coupling between aerobic potential
of the muscle and its capillary supply has been chal-
lenged by Maxwell and colleagues (482). They studied
fiber composition, oxidative potential of whole muscle,
and degree of capillarization of various skeletal mus-
cles from five species and found no significant relation
among any of the variables. This conflicts with a large
number of other reports, but it must be pointed out
that Maxwell et al. did find significant correlations
among several ofthese variables within a species (482).
The metabolic potential of a given muscle fiber type
may vary considerably between species, and indeed
may vary within a given animal. Thus the approach
taken by Maxwell et al. may not be the most fruitful
to elucidate the problem of a coupling between aerobic
potential of a fiber and its capillary supply (482).
From among variables used to quantitate capillari-
zation, the question of which serves as the best indi-
cator of diffusing conditions is still unsettled. Based
on a comparative study of various species, Plyley and
Groom (561) have come to the conclusion that the
number of capillaries per fiber is an appropriate meas-
ure, whereas others favor Krogh's concept of a capil-
lary and its "diffusing" cylinder (6, 226, 295). Although
it appears essential to include an estimate of diffusing
distance, it is not immediately apparent whether the
critical distance is to the center of the muscle fIber or
ADAPTABILITY: METABOLISM AND PERFORMANCE 605
to the most distant point between capillaries along the
periphery of a fiber in cross section; the point being
that mitochondrial density is largest underneath the
sarcolemma with fewer mitochondria found centrally
(364,422). What adds to the importance of this ques-
tion is that although it is commonly believed that the
diffusion of oxygen is the key factor, there may be
situations during exercise where substrate uptake,
release of a metabolite, or heat dissipation is just as
essential.
Capillary Length and Diameter
There are few detailed studies on capillary length
and diameter for most species, and for man they are
nonexistent. Thus available information on capillary
surface area and volume in skeletal muscles is limited.
In the early studies the capillaries were estimated to
account for 10% or more of total muscle volume, which
was much too high a value as could be deduced from
measurements oftotal vascular volume (535). Pappen-
heimer et al. (536) estimated the values to be approx-
imately 0.1 of those previously reported; i.e., capillary
surface area was estimated to be 0.7 m 2 j 100 g muscle
tissue and the volume 1.6%. Later studies have all
given estimates of the same order of magnitude al-
though there appears to be some variation related to
species and muscles studied (111, 285, 492, 728).
The most direct measurements are obtained with
vital microscopy. In the rabbit's tenuissimus muscle
the diameter averages 5.4 !-tm and is slightly narrower
at the arteriolar end of the capillary [4.7 urn (196)].
Cat tenuissimus muscle capillaries have the same di-
ameter, whereas those of the dog gastrocnemius (4.2
um) and rat extensor hallucis proprius (4.8 !-tm) are
slightly smaller (477, 507). Length of muscle capillaries
varies markedly in the same capillary bed, and by
comparing various muscles and muscles in various
species figures between 100 !-tm and 2,000 !-tm have
been reported (196, 507, 509). Assuming a length of
1,000 !-tm for mean capillary length in human muscle
and a mean diameter of 6 !-tm (slightly less than the
mean diameter of a red blood cell), this will give a
capillary surface area of 0.62 cmt/cm" muscle in a
muscle with 330 capillaries/mm", In muscles with pre-
dominantly FT fibers this value may be slightly less
and in muscle with many ST fibers somewhat higher.
Based on the same assumptions capillary volume in
human skeletal muscle is around 1%.
In these estimations of capillary surface area and
volume it is usually assumed that the capillaries are
straight, as the most precise numbers for length and
diameter of the capillaries are obtained on thin and
flat muscles. The capillaries may have a rather tor-
tuous arrangment, especially in muscles with many
ST fibers. Thus an underestimation of the true surface
area and volume of the capillaries is likely in these
muscles. All of these estimates concern the total num-
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
given time.
Use and Disuse
CAPILLARY DENSITY. Long before systematic studies
of the effect of training on skeletal muscle capillariza-
tion were performed, it was noted that the domesti-
cated animal held in sheds or cages had fewer skeletal
muscle capillaries than its counterpart living in the
wild (65, 710). Early training studies on rats also
revealed a pronounced increase in the number of skel-
etal muscle capillaries, although the significance of
some of these early reports can be questioned as
exceptionally high capillary counts were observed. No
doubt exists, however, that there is a true proliferation
of capillaries associated with an enhanced physical
activity level in these nonhuman species (for refer-
ences, see ref. 370). Further, the adaptation is a local
response, i.e., it occurs in the exercised muscle and
only around those muscle fibers that are recruited in
the training schedule.
For a long time comparable data were not available
in man. In the first systematic study, cross-sectional
material of sedentary men and endurance athletes was
examined, and the same number of capillaries per fiber
was observed in both groups (342). Further, in a study
where the physical activity level was varied, no sig-
nificant changes in any of the variables to stimulate
capillarization could be detected (601). In both ofthese
studies electron microscopy was used to identify the
capillaries. Judged by the low numbers of capillaries
per fiber reported by these investigators, all capillaries
may not have been identified.
More recent studies using both electron microscopy
and histochemistry have demonstrated that human
skeletal muscle adapts to use by increasing the number
of capillaries (6, 73, 385, 387, 402, 521, 523). In fact all
variables (capillaries per fiber, capillaries per square
millimeter, and number of capillaries found around a
fiber) are increased. As the latter two variables also
are a function of muscle fiber size, the variable most
frequently used is capillaries per fiber. This indicator
of capillarization is in trained muscle closely linked to
whole-body maximal oxygen uptake of a subject (Fig.
25), and alteration in activity level causing a change in
maximal oxygen uptake results in a parallel change in
the number of capillaries per fiber. From such plots it
is apparent that the percentage changes of these two
variables are comparable. A doubling of maximal ox-
ygen uptake corresponds approximately to a doubling
of the number of capillaries per fiber. Including the
size of the fibers in the evaluation of diffusing condi-
tions of skeletal muscle with training makes the pic-
ture somewhat more complex but also gives a deeper
insight into the problems. In most training studies of
the endurance type, skeletal muscle fibers are slightly
enlarged. If in the exercise all fiber types are involved,
both the number of capillaries around the various fiber
types and the size of the fibers are increased (6, 402,
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
(Fig. 26). The present reduction in diffusing area is
found to be largest for FT (FT b ) fibers. This is quite
similar to the observation for the activity of mitochon-
drial enzymes. In untrained muscles FT (FTb ) fibers
have the largest fiber area per capillary and the lowest
level of oxidative capacity, but with use these fibers
adapt and become almost indistinguishable from ST
fibers for these variables. This supports the concept of
Romanul and others (569, 588, 590) that there is a
close coupling between the number of capillaries and
the capacity for oxidative metabolism of the fibers
they supply. Further, in experiments where the time
course for changes has been followed in rat and rabbit
muscle during chronic stimulation, it appears as if the
capillaries begin to proliferate before changes can be
noted in the oxidative enzymes. Just as importantly,
it proves that the FT fibers have the ability to adapt
to aerobic metabolism, which is similar to the metab-
olism of ST fibers.
In the experiments with chronic stimulation of a
muscle it was found that along with enhanced aerobic
potential of the muscle fibers and increased number
of capillaries adjacent to a fiber, the fibers also became
slightly smaller, thereby contributing to the shortening
of diffusing distances in the muscle (134, 135). Also,
with endurance-type training in animals as in stan-
dard-bred horses and rats, the mean muscle fiber area
is reduced in trained muscles [(110, 204); unpublished
observations by P. Henckel on horses]. This reduction
is mainly a function of smaller FT (FG and FOG)
fibers. Similar findings from man are available. In
well-trained endurance swimmers, mean muscle fiber
area was the smallest in the most trained muscles
(523), and in marathon runners the areas of muscle
fibers in the gastrocnemius muscle were also small
(367). Further, 2 wk of no training caused the muscle
fibers of the gastrocnemius to become slightly larger
(367). These findings may support the notion that the
distance to the center of the muscle cell is a critical
factor. Whether it is the transport of gas or substrate
that is crucial is, however, still obscure. Because
myoglobin markedly enhances the oxygen transport
within the cell (724) and is elevated with enhanced
oxidative capacity, the reduction in diffusing distances
of substrates other than oxygen may be the crucial
limiting factor. .
The effect of inactivity on muscle capillarization is
less well studied in man (Fig. 26). The picture that
emerges from available detraining studies or studies
where a limb is placed in a cast is that the number of
capillaries per fiber is reduced. Notably it appears as
if early in the time course the reduction in the number
of capillaries is slightly slower than a possible change
in fiber size, resulting in slightly shorter diffusing
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-
tion (425). With tenotomy, reduction in capillary den-
sity has also been observed (411, 412).
CAPILLARY LENGTH AND DIAMETER. The only exact
data available are from studies on rats and rabbits,
where muscles have been chronically stimulated and
evaluated with vital microscopy (509). Along with a
quite rapid proliferation of capillaries, which is notice-
able within days, there is a reduction in mean capillary
length. The increase in number of capillaries is larger
than the decrease in length. The capillary surface area
and volume do enlarge with increased use of the
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.
In addition to increased branching, as a result of
more muscle activity the capillaries may become more
tortuous (13). Precise data on this point are not avail-
able, however.
MYOGLOBIN. The redness of a muscle fiber depends
on its myoglobin content, and for a long time this has
been the basis for classifying muscle fibers. The oxi-
dative capacity of the muscle fiber and its myoglobin
content are closely coupled in a large range of animal
species (448-450). With physical training in rats myo-
globin content is increased parallel to the enhance-
ment of the aerobic enzymes (537). Further, an in-
crease is only observed in muscles engaged in the
training program. Studies on human muscles are
scarce. In preliminary reports by Jansson and Sylven
(400) a clear-cut difference was observed when ST and
FT fibers were compared, with the mean value for ST
fibers being 60% higher than for the FT fibers. So far,
however, they have been unable to detect a training
effect, i.e., when examining cross-sectional material of
trained bicyclists with sedentary people, the same
myoglobin content is noted in the leg muscles although
a difference in mitochondrial enzyme is noted (E.
Jansson, personal communication).
Regulation
Little is known about the factors involved in capil-
lary proliferatioh. Myrhage and Hudlicka (509) cite
Ashton (20) saying that "endothelial cells themselves
are in some way directly sensitive to oxygen-multi-
plying at low O2 levels, resting at normal O2 levels, and
dying at high Oe concentrations." They base this belief
in tissue partial pressure of Oz (Po-) being the crucial
variable on the same reports of high capillary counts
in skeletal muscle of animals living at or exposed to
high altitude (14, 112, 699). Other studies have re-
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
subjects (602). Bars Band C show values before and after 8 wk of
conditioning (6, 425). Bar D shows values from well-trained men
(367,398,523,602). Bars M and N are values from subjects decon-
ditioned for 7-14 days (ref. 425; B. Saltin, unpublished observations).
V02 max below bars M and N was estimated from heart rate response
to submaximal exercise (subjects were recovering from minor knee
injury).
laries are formed when exposed to low oxygen pressure
in inspired air. Systematic studies in various species
by Banchero and associates (30, 164, 631, 632, 635)
clearly demonstrate that the larger number of capil-
laries per square millimeter is due to the decrease in
the cross-sectional size of the muscle fibers. The num-
ber of capillaries per fiber is unchanged in their stud-
ies. The same appears to be true for human muscle
(604). When sea-level residents stay at high altitude
(elevation 3,700 m) for months, the muscle fibers be-
come slightly smaller but the number of capillaries per
fiber is unchanged (Fig. 27). Further, permanent resi-
dents at this altitude do not have a high number of
capillaries per fiber, but they have small muscle fibers
resulting in high values for capillaries per square mil-
limeter. When the high-altitude residents are divided
into physically inactive and physically active, the lat-
ter group has the higher number of capillaries per
fiber, similar to the results found in sea-level residents.
Thus it appears likely that tissue oxygen tension is not
the key factor for capillary proliferation.
Unfortunately no other obvious alternative for a
stimulus and regulatory factor has been suggested. In
tissue injury some substance is thought to be released,
serving as a stimulus for capillary proliferation (68);
but with increased use of a muscle, no signs of tissue
Muscular Size
The capacity of skeletal muscle to develop tension
per unit of cross-sectional area is not altered by train-
ing. At the molecular level this implies that the tension
developed per cross-bridge interaction is constant.
This is what could be anticipated. A large variation
does exist in the number of fibers contained in the
same muscle of man and rat. This is probably a func-
tion of genetic endowment and a likely factor in lim-
iting the maximal growth potential of a muscle. As
fiber number is uninfluenced by the activity level, the
only resource available for increasing total muscular
strength is for the muscles to increase in cross-sec-
tional area (427). This is accomplished by a hypertro-
phy of the existing muscle fibers. It may appear that
it would be just as logical to have mechanisms for
increasing the number of fibers in a muscle rather
than restricting the number of those present either at
or shortly after birth. There are, however, a number
of arguments against the efficacy of adding fibers to
preexisting muscles. First, this could disturb the exist-
ing architecture in the muscle by having to provide for
new attachments on the bone or tendons that serve as
origin and insertions. If the fibers arose within the
muscle without appropriate attachments they would
be ineffective (506). Second, and perhaps of greater
importance, is the problem of how they would be
innervated and incorporated into preexisting motor
units. A lateral sprouting of the existing motor units
might also result in reducing the capacity for neuro-
muscular coordination.
Although the capacity for skeletal muscle to enlarge
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
the torque that a muscle can develop around a joint.
This is because for muscles with pennate fiber arrange-
ments the angle of attachment to the tendon becomes
greater as they are enlarged (57,490). Since the force
developed along the long axis of the muscle depends
on the angle of attachment, this change in angle will
result in a diminution in the tension transferred to the
tendon. A mathematical model illustrating this prin-
ciple was published by Lindhard (456). Although in-
creases in strength can be closely related to changes
in the total cross-sectional area of a muscle, there are
many reports of increases in muscular strength with-
out changes in muscle bulk. This can be explained on
the basis of an increased capacity for motor unit
recruitment and activation.
610 HANDBOOK OF PHYSIOLOGY - SKELETAL MUSCLE
Substrate Stores
The resting levels of ATP and CP in skeletal muscle
of man are in the range of 5 and 20 mol/kg wet wt,
respectively, and these stores are influenced by the
state of training only to a very minor extent. The
amount of energy contained in the phosphagen stores
is very small and would only support 3-4 s of maximal
contractile activity. With a few exceptions even a
doubling of these stores would have little physiological
meaning. Instead it would be more judicious to enlarge
the capacity for resynthesizing ATP through an in-
creased capacity for energy release via end-terminal
oxidation and/or glycolysis.
That the energy per unit of weight in ATP and CP
is quite small supports such a conclusion. Further, by
keeping the ATP-ADP-AMP pool low in muscle, any
changes among these components result in a large
change in their ratio, which is important in view of the
regulatory function this ADP/ ATP ratio has on the
metabolic reactions both in the cytosol and in the
mitochondria.
The glycogen stores of the muscle are only slightly
elevated as a result of changed activity level. Any
specific role of this increase for brief exhaustive exer-
cise, where muscle lactate reaches levels of 20-25
mmol/kg wet wt, can hardly be anticipated, as muscle
of sedentary man already contains approximately 80
mmol/kg wet wt of glycogen. In repeated efforts a high
initial glycogen storage may be of some importance.
The question can then be asked, how important are
changes in the intramuscular energy stores in terms of
the capacity for aerobic energy production? This can
be considered from two standpoints. First, how would
an augmentation of the local energy reserves relate to
the maximal work capacity of a muscle if this were the
only source of substrate? The aerobic capacity of
skeletal muscle is a function of the maximal flux of
substrates through the oxidative systems of the mito-
chondria and the supply of oxygen. The maximal
substrate flux through the metabolic pathways can be
estimated from the V max of selected enzymes (see
Table 1). From such data it can be estimated that the
maximal substrate flux through the oxidative enzymes
would require an oxygen uptake of about 850 ml- kg-I.
min- I and a blood flow of about 5 liter-kg r'<min"
(based on an oxygen extraction of 170 ml /liter of
blood). If this oxygen uptake can be attained by man
it is only with exercise of a small muscle group (1).
With exercise (such as walking, running, or cycling)
that is sustainable for 8-10 min, the oxygen consump-
tion may average about 150 ml/kg of active muscle
per minute. When the exercise intensity is about one-
half that sustainable for 8-10 min, it can be performed
for many hours. If fully oxidized, the glycogen and
triglyceride stores of human muscle are equal to about
200 and 80 kJ/kg wet wt, respectively. At the maximal
rate of oxidation with a small muscle group, the local
energy stores would last 17-18 min. Such efforts, how-
ever, cannot be sustained for this period of time, and
factors other than the local availability of substrate
must be limiting. Thus it would appear that augment-
ing the local energy stores, whether this be as glycogen
or triglyceride, would be of little importance for max-
imal efforts. With short, intense exercise there is a
rapid depletion of glycogen from the FT fibers in
skeletal muscle. A failure to sustain multiple bouts of
such exercise may be related to an exhaustion of the
local glycogen in the FT fibers. An elevation in the
glycogen stores could forestall exhaustion in such ac-
tivities.
A second aspect of the importance of changes in
intramuscular energy stores relates to submaximal
exercise. As indicated, the exercise capacity of man at
power outputs of about 50% of maximal is several
hours. The immediate energy stores of muscle are
sufficient for up to 200 min of such exercise. Thus it is
obvious that extramuscular substrates also are impor-
tant. This has been demonstrated in experiments
where mobilization of fats has been inhibited. At ex-
haustion the carbohydrate stores of the body are
nearly depleted (341), and the importance of this en-
ergy store as a determinant of exercise capacity has
been demonstrated (51,222,260,577, 725). Consump-
tion of a fat and protein diet decreases exercise toler-
ance by about 25%, whereas exercise capacity was
doubled following consumption of a high-carbohydrate
diet (51, 271). Subsequent experiments have estab-
lished that these dietary manipulations alter the gly-
cogen store of the muscle and that a linear relationship
existed between exercise capacity and the muscle gly-
cogen concentration (51). The role of stored triglyc-
eride is unknown. It is, however, well known that
increases in the local glycogen store can increase ex-
ercise capacity. This is even more important when
coupled with the increased oxidation of fat that occurs
with training.
Enzyme Activities
ANAEROBIC METABOLISM. There are reports of in-
creases in the activities of some enzymes in the gly-
colytic pathway. In some instances these changes are
small and appear to exist in only select enzymes of the
system. Moreover in some cases the enzymes that
have been reported to increase are not those whose
activity is known to be regulated (PHOS, PFK) and
which thus exert control over the flux of substrate
through the system. Overall the data available con-
cerning adaptations in the glycolytic system are less
certain than those for the enzymes for end-terminal
oxidation.
An increase in the enzymes for glycolysis has an
unknown role in the overall economy of the metabolic
response to exercise. All fiber types are very well
endowed with such enzymes. For example, the PFK
activity of the ST and FT fibers of human muscle has
been reported to be 25 and 50 mmol.kg-I.min- I (203).
 CHAPTER 19:
This enzyme usually has an activity similar to that of
PHOS. Both enzymes are regulated and are generally
believed to regulate the flow of substrate through the
glycolytic pathway. If fully activated this would result
in the production of 50 and 100 mmol Iactate-kg":
min" for the ST and FT fiber, respectively. These
values far exceed those that have been observed during
maximal voluntary muscular activity. It has been es-
timated that a 5% activation of PHOS could account
for the maximal lactate production in skeletal muscle
if glycolysis depended on PHOS (220). Further aug-
mentation of this system would not seem useful. More-
over it does not appear that increasing the total
amount of enzyme available would increase the pre-
cision for regulating substrate flux through the system.
As pointed out, the concentration (activities) of the
enzymes of the Embden-Meyerhof pathway is very
high in most skeletal muscle, particularly in the FT
fibers. This activity would appear to be greater than
that which would ever be required for the degradation
of glycogen. This brings up the question of why these
enzymes are maintained at such high levels. This
metabolic pathway would be most important during
periods of short, intense muscular activity where a
major part of the ATP production was derived from
the degradation of glycogen to lactate. During such
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
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
efforts V' OZmax is reached earlier, however, and there is
a continued elevation in the blood lactate. This sug-
gests that lactate per se is not responsible for termi-
nating the exercise, nor are the enzymes for metabo-
lism significantly inhibited.
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
man (432). When these animals dive there is an almost
complete shunting of the blood from the peripheral
muscles to the heart, lung, and brain circuit. The
exercising muscles may be nearly ischemic. Muscular
activity can continue for rather long periods of time
under these conditions. After such exercise the muscle
lactate may exceed 50 mmol/kg. This suggests that an
end-product inhibition of the glycolytic pathway prob-
ably does not occur or is of only minor importance in
those animals.
The question remains as to why the very high
ADAPTABILITY: METABOLISM AND PERFORMANCE 611
concentrations of enzymes exist in the glycolytic path-
way. These levels are obviously higher than would be
required to produce the substrate flux that occurs
through this pathway. It would appear that the answer
lies in the overall regulation of this system. There are
rate-limiting enzymes in this pathway. However, most
of the enzymes are of the equilibrium type and obey
Michaelis-Menten kinetics and thus are substrate con-
trolled (Fig. 29). With such enzymes the higher the
enzyme concentration the greater will be the activity
at very low substrate concentrations. This allows for
a better control over the system. For example, with an
enzyme such as pyruvate kinase the activity of which
is about 400 {.tmol of substrate converted per gram per
minute, it is highly unlikely that a substrate concen-
tration could ever be reached to produce Vmax. How-
ever, a low substrate concentration, for example, 10%
of the K m , would induce an activity of about 40 umol
of substrate split per minute per gram. This activity is
higher than that required for the maximal rates of
lactate production that occur during heavy exercise.
With high enzyme levels it is possible to attain high
rates of substrate fluxes at low substrate concentra-
tions. Since there are a number of enzymes involved
in the pathways for ATP production, the induction of
high activities via elevations in substrate levels would
Vmax at 2 X enzyme conc.
-------- --- ---
v
o
CIo
>
c:
o
v
a:'"
CIo
Sub s t ra t e c o nc e n t r at i cn in rnore s r l
FIG. 29. A representation of the influence of changing the total
enzyme concentration on the specific activity based on the rate (V,).
The velocity and any substrate concentration [S] can be estimated
from the Michaelis constant (K m) and the maximal velocity (Vmax)
for the equation V, = Km[:][S]' Vmax. With a doubling of enzyme
concentration, velocity of the reaction will be doubled at any sub-
strate concentration. This relationship would be most important at
low substrate concentrations where substrate could thereby be more
efficiently directed into end-terminal oxidative pathways. Con-
versely with a reduction in enzyme concentration such control
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
pressure within the cell would be unacceptable.
AEROBIC METABOLISM. In addition to substrate levels
and mitochondrial enzymes, the role of oxygen deliv-
ery is important for a discussion of the aerobic energy
yield in muscle. To thoroughly discuss this subject we
need to summarize some of the adaptations that occur
within the cardiovascular system as a response to
varied levels of physical activity. From the results in
Figure 30 it is apparent that at maximal exercise
(running or bicycling) that elicits maximal oxygen
uptake both systemic cardiac output and a widening
of the arteriovenous difference contribute to the im-
proved maximal oxygen uptake. After a short period
of adaptation to endurance training these two factors
increase to the same extent. After a longer period of
training, enlargement of the cardiac output contrib-
utes the most to the increased maximal oxygen uptake.
Muscle capillary density and mitochondrial enzyme
activities are enhanced both after shorter and longer
periods of adaptation. The percentage increase in cap-
illarization occurs in parallel with maximal oxygen
uptake, whereas the increase in mitochondrial enzyme
potential is far in excess. The question then is whether
these changes in the muscle are necessary to increase
maximal oxygen uptake. Since close relationships exist
among the degrees of capillarization, the activity of a
marker enzyme for oxidative capacity, and maximal
oxygen uptake in experimental material with large
variations in training studies, many researchers use it
as a criterion to illustrate the importance of these
variables in attaining maximal oxygen uptake.
It is true that many links in the transport of oxygen
to the tissues are closely related, but this does not
mean that they are limiting (63, 636). Exercise with a
single muscle group, such as the knee extensor mus-
cles, illustrates this problem. In a sedentary person
blood flow to these muscles at maximal exercise may
average 2,000-3,000 ml- kg- I of muscle. min -I, V02may
attain values of 400-500 ml 02kg- 1 of muscle.min-I,
while the arterial-femoral venous oxygen difference is
maintained at around 160-180 ml/liter (1). Thus when
the capacity of the cardiovascular system can be di-
verted to a small, maximally activated muscle mass,
considerably larger blood flow and oxygen uptake
(milliliter per kilogram of active muscle) are observed
than in ordinary whole-body exercise when systemic
cardiac output is shared by a much larger muscle
mass. Although blood flow through the knee extensors
is tremendous, an extremely wide arterial-femoral ve-
nous oxygen difference is maintained. Taken in total,
we conclude from these results that neither the capil-
larization of the muscle nor the concentration of mi-
tochondrial enzymes are limiting to whole-body aero-
bic power in healthy man.
If we cannot ascribe any significant role to the
adaptation in capillarization or mitochondrial enzyme
concentrations for attainment of maximal oxygen up-
take, why do these variables change so dramatically
 CHAPTER 19:
in response to physical training? An obvious effect of
increasing the number of capillaries, and also the
observed small decrease in the size of the muscle fibers
with extreme endurance training, would be to reduce
the diffusion distances within the muscle. This may
be crucial for gas and substrate transport, especially
FFA, from the blood to the muscle cell.
In the trained state the number and volume of
mitochondria increase, which increases the surface
area for the exchange of metabolites, cofactors, and
end products between the cytosol and the mitochon-
drial matrix. Of particular interest here might be an
increased capacity for the transport of fatty acids into
the mitochondria and the ATP out into the cytosol.
This could in part be responsible for the increased use
of FFA, the decreased rate of glycogen depletion, and
the lower lactate levels that occur in response to a
standard exercise test after training. These differences
occur despite lack of change in oxygen uptake and
cardiac output at standard work loads before and after
training.
A possible effect of increasing the activities of oxi-
dative enzyme in muscle would be to elevate the
capacity for the low oxidative fibers for terminal oxi-
dation. Thus the FT fibers, and particularly the FT b
fibers, could more effectively utilize the intracellular
glycogen stores and perhaps rely to a greater extent
on the oxidation of FFA during prolonged exercise.
This would be important where such fibers ultimately
are recruited during prolonged exercise, and during
more intense exercise, where there may be engagement
of these motor units from onset of exercise.
Although the above considerations might be impor-
tant for the understanding of the overall metabolism
of skeletal muscle during exercise, they fail to ade-
quately explain why there is such a large increase in
the oxidative capacity. The answer to this question
could be related to how enzyme concentration influ-
ences the sensitivity of enzyme regulation. Thus with
higher enzyme concentrations it would be easier to
regulate the oxidative system on the basis of a sub-
strate and cofactor regulation of the enzymes. This
effect would be important for both the nonrate-Iimit-
ing and the rate-limiting enzyme reactions. The un-
derlying principle is that most enzyme reactions ap-
pear to obey Michaelis-Menten kinetics (256). Under
these conditions increases in substrate exert profound
control over the reaction rate at the lower levels of
substrate (Fig. 29). The substrate concentration that
produces 50% of the V rna x is the well-known Michaelis
constant (Krn ) . This figure illustrates that by doubling
the enzyme concentration the reaction velocity at K rn
will also be doubled. This is true since K rn is independ-
ent of enzyme concentration. Further, at very low
substrate levels large differences in the reaction rate
in response to a given substrate concentration would
be realized by increases in total enzyme content. Since
the substrate levels needed to attain V rna x for a given
enzyme are probably never attained in vivo, the ab-
solute V rna x for a given enzyme is probably of minor
ADAPTABILITY: METABOLISM AND PERFORMANCE 613
importance, and most enzymes function at most at
about 50% of the Vmax or near the K rn in the intact
system. Another illustration of this concept is that to
elicit an increase in the enzyme velocity from 10% to
90% of the Vrnax requires an 81-fold increase in sub-
strate concentration. Such a flooding of the tissue with
any metabolite is extremely unlikely. However, an
elevation in the total enzyme concentration would
increase the sensitivity for control at low substrate
levels and also increase total activity. This could result
in a more efficient use of the substrate stores by
directing them through the oxidative pathways with
the result being to maintain a constant ADP/ ATP
ratio in the cytoplasm thereby inhibiting anaerobic
glycolysis at the level of PFR. Such a fine tuning of
the control of oxidative metabolism could be respon-
sible for the lower respiratory exchange ratio and
lactate levels in muscle and blood that occur during
exercise after training. Conversely a decrease in phys-
ical activity with a resultant loss of oxidative capacity
would have an opposite effect on metabolic control.
Could the increase in the enzymes for oxidation be
operative in controlling the entry of substrates into
the citric acid cycle? The key enzyme for such sub-
strate entry is thought to be citrate synthase (722).
The activity of this enzyme increases with endurance
training; it is also regulated by the levels of both
acetyl-CoA and oxaloacetate (722). This is not to imply
that substrate flux through the citric acid cycle is
under such simplistic control but only to point out
that an increased enzyme concentration would facili-
tate this control. It is known, for example, that the
flux of substrate through the citric acid cycle is a
function of the coordinated control of citrate synthase,
isocitrate dehydrogenase, and a-ketoglutarate dehy-
drogenase (722). These activities are linked not only
to oxaloacetate and acetyl-CoA concentrations, but
also to the NAD/NADH ratio and citrate levels. When
the NADH level in the mitochondria is high, due
either to a lack of oxygen or to ADP, isocitrate dehy-
drogenase is inhibited and citrate accumulates. Such
an elevation of citrate concentration results in an
increase in the K of citrate synthase. With the oxi-
dation of NADH the citrate level will fall and the K rn
of citrate synthase will be lowered. The increased
enzyme concentration would aid in the directing of
acetyl-CoA units derived either from decarboxylation
of pyruvate or /i-oxidation into the citric acid cycle.
Since most of the enzymes of the citric acid cycle have
been shown to increase in skeletal muscle in response
to training, the overall effect would be to increase the
response of this system to lower substrate levels.
The question can be asked, why would an organism
adapt to an increased metabolic demand by increasing
the level of proteins that would require energy for
synthesis and maintenance rather than by simply stor-
ing more intramuscular substrates? In the latter in-
stance it might be possible to raise the metabolite
levels during periods of maximal activity to attain
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
V max of the enzymes are unreasonably high and might
cause an increase in osmolality. In such a case this
could be complicated because the intramitochondrial
and cytoplasmic metabolic reactions may occur at
different rates. Just as important is the possibility that
glycogen, although it contains rather large amounts of
energy per unit weight, will create a weight distur-
bance because it is stored with 2-3 g of water per gram
of glycogen. Migrating birds and insects have a metab-
olism almost completely geared to fat metabolism
(719). It is likely that in terrestrial animals the overall
economy of movement calls for limitation in the stor-
age of glycogen.
The stores of lipids in human skeletal muscle are
rather small and no changes due to increased physical
activity levels are apparent. Why this energy source is
kept so low in the muscles of man and rodents is
presently unknown. Instead, especially in man the
extramuscular lipid stores are high and would, in in-
dividuals of normal body weight, support many hours,
in fact days, of submaximal exercise.
In contrast, glycogen is stored only in small amounts
outside the skeletal muscles, the total in the liver being
only 40-70 g (373). The primary purpose of this gly-
cogen store is to maintain blood glucose concentration
as a continuous supply to the nervous system. Its role
for muscle is limited. In fact at least two regulatory
mechanisms are brought into play during exercise to
minimize its uptake by skeletal muscle. These are a
reduction in plasma insulin levels and an elevation in
the intracellular concentration of glucose 6-P0 4 , which
inhibits hexokinase and the phosphorylation of glu-
cose needed for its transport across the cell membrane.
Summary
The stage is then set. In submaximal exercise with
limited amounts of glycogen (also after dietary manip-
ulation) and with the predominant fraction of the
lipids stored outside the muscle cell, the ultimate
factor that determines the intensity and duration of
work is the body's capacity to utilize extramuscular
fat stores. There are at least five steps required for the
transport of FFA from the adipocytes to the skeletal
muscles, where the lipids are being finally oxidized in
the mitochondria. These are 1) the release from the
fat cell, 2) transport to the muscle via the blood, 3)
transport from the capillary across the interstitial
space to the muscle cell, 4) transport into the muscle
and mitochondria, and 5) oxidation by the mitochon-
dria. Both in the untrained and in the trained state
the mobilization of lipids appears to be sufficient, and
the exercising muscles are offered ample amounts of
FF A. Only a very small percentage (3%-5%) of the
FFA that is offered by the blood is taken up by the
muscle (258, 269). This is also true in situations lacking
all other substrates, indicating that the limitations in
the utilization of FFA lie either within the muscle or
in the transport of the FFA from the blood into the
muscle cell (510, 591). There may be a larger FFA
uptake by trained muscle but if this is so, it is within
the methodological variation and thus has not been
substantiated (332, 333). It is not known which of the
three remaining possibilities for limiting the uptake of
FFA by skeletal muscle is the most important. Pres-
ently, it appears that the transport of FFA through
the interstitial space with its low protein concentration
may constitute the major hindrance. For obvious rea-
sons (colloid osmotic pressure and hydrostatic pres-
sure balance over the capillary wall) interstitial protein
concentration cannot be elevated. With training, adap-
tations take place on both sides of this hindrance, by
increasing the number of capillaries and by elevations
in mitochondrial volume and the capacity for f3-oxi-
dation. The importance of these adaptations is illus-
trated in Figure 31, which shows that when subjects
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:
utilization of FFA is greater and the production of
lactate less by the trained leg in spite of the fact that
both legs were offered similar amounts of oxygen and
FFA. Of note is that the increase in mitochondrial
protein is maintained as long as the training stimulus
persists. After termination of training the "excessive"
metabolic apparatus is rapidly disassembled and the
muscle returns to the nontrained state.
Part of the answer to why increases occur in total
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