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Respiratory Physiology & Neurobiology 151 (2006) 242–250

Consequences of exercise-induced respiratory muscle work夽


Jerome A. Dempsey ∗ , Lee Romer, Joshua Rodman, Jordan Miller, Curtis Smith
John Rankin Laboratory of Pulmonary Medicine, Department of Population Health Sciences, University of Wisconsin,
Madison, WI, Unites States

Accepted 16 December 2005

Abstract

We briefly review the evidence for a hypothesis, which links the ventilatory response to heavy intensity, sustained exercise-to-
exercise performance limitation in health. A key step in this linkage is a respiratory muscle fatigue-induced metaboreflex, which
increases sympathetic vasoconstrictor outflow, causing reduced blood flow to locomotor muscles and locomotor muscle fatigue.
In turn, the limb fatigue comprises an important dual contribution to both peripheral and central fatigue mechanisms, which
contribute to limiting exercise performance. Clinical implications for respiratory limitations to exercise in patients with chronic
obstructive lung disease (COPD) and chronic heart failure (CHF) are discussed and key unresolved problems are outlined.
© 2006 Elsevier B.V. All rights reserved.

Keywords: Respiratory muscle work; Diaphragm; Exercise; Fatigue; Blood flow

1. Hypothesis 2. Near-ideal characteristics/adaptations of the


respiratory muscles
Our hypothesis is shown in the flow chart in Fig. 1.
It explains our view that the demand placed on the res- We start with the important qualification that the
piratory muscles because of the ventilation required by diaphragm and to a lesser extent the expiratory abdom-
heavy intensity, sustained exercise in healthy subjects inal muscles possess unique characteristics that make
will contribute significantly to exercise performance them the most fatigue-resistant of all the skeletal mus-
limitations through its effects on limb vascular conduc- cles. The diaphragm has a very high aerobic enzymatic
tances and blood flow and locomotor muscle fatigue. capacity, multiple sources of blood supply, a unique
resistance to vasoconstrictor influences on vascular
夽 This paper is part of a special issue entitled “New Directions in diameter and therefore a substantial fatigue resistance.
Exercise Physiology,” Guest Edited by Susan R. Hopkins and Peter Furthermore, with progressively increasing exercise
D. Wagner. expiratory muscle activation reduces end-expiratory
∗ Corresponding author at: 4245 MSC, 1300 University Avenue,

Madison, WI 53706-1532, United States. Tel.: +1 608 263 1732;


lung volume thereby sparing inspiratory muscle func-
fax: +1 608 262 8235. tion in two ways (Johnson et al., 1992; Johnson et
E-mail address: jdempsey@wisc.edu (J.A. Dempsey). al., 1993): (a) the diaphragm and other inspiratory

1569-9048/$ – see front matter © 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.resp.2005.12.015
J.A. Dempsey et al. / Respiratory Physiology & Neurobiology 151 (2006) 242–250 243

3. Exercise-induced diaphragmatic fatigue

Despite the substantial aerobic capacity of the


diaphragm this muscle will show significant fatigue
during exercise sustained to exhaustion at intensities
greater than 80% of V̇O2MAX . This has been docu-
mented using the bilateral phrenic nerve electrical stim-
ulation technique (1–20 Hz). The trans-diaphragmatic
pressure evoked by supra-maximal stimulation imme-
diately following exercise is reduced 25–50% below
pre-exercise baseline and takes about 2 h to recover
(Johnson et al., 1993). This exercise-induced diaphrag-
matic fatigue is in part due to the high levels of
diaphragmatic work that must be sustained throughout
Fig. 1. Hypothesis: ventilatory requirements DURING sustained,
high intensity exercise, as shown by the finding that
high intensity exercise in healthy subjects leads to diaphragm fatigue diaphragmatic fatigue was prevented when diaphrag-
and eventually to compromised limb blood flow and fatigue (see text). matic work was reduced by using a proportional assist
The estimate of the fraction of the cardiac output (and V̇O2 ) devoted ventilator (PAV) throughout the exercise (Babcock et
to the respiratory muscles during exercise at peak work rate is derived al., 2002). However, the diaphragmatic work, per se,
from measurements of muscle blood flow via microspheres in ponies
(Manohar, 1986), from the oxygen cost of respiratory muscle work in
is not sufficient to explain the diaphragmatic fatigue,
humans (Aaron et al., 1992) and from the reductions in V̇O2 and CO because when the resting subject mimicked (by use of
observed during respiratory muscle unloading in highly fit humans visual and auditory feedback) the magnitude and dura-
at maximal exercise (Harms et al., 1998). tion of diaphragmatic work incurred during endurance
exercise, fatigue did not occur (Babcock et al., 1995).
In fact, fatigue did not occur until diaphragmatic
muscles are lengthened and operate near their optimal work was voluntarily increased two-fold greater than
length for force generation; (b) tidal volume rises by that required during maximum exercise. Why is the
encroaching on both inspiratory and expiratory reserve diaphragm so susceptible to fatigue during exercise?
volumes thereby allowing lung volume changes to We think this effect reflects the requirement that the
occur over the most linear and mechanically efficient diaphragm must compete with the locomotor muscles
portion of the pressure:volume relationship. Equally for the available blood flow during heavy intensity exer-
important, accessory respiratory muscles are progres- cise, thereby promoting an inadequate oxygen transport
sively recruited with increasing ventilatory demand in and fatigue of the diaphragm.
exercise, thereby sharing the load needed to support
exercise hyperpnea.
The results of these extraordinary structural char- 4. Exercise-induced diaphragmatic fatigue:
acteristics of the respiratory muscles combined with cardiovascular effects
the neural control of inspiratory and expiratory mus-
cle function and lung volumes means that – with few In prolonged high intensity exercise, hyperventila-
exceptions – pressures generated by the inspiratory tion usually prevails throughout, demonstrating that
muscles during even heavy intensity exercise stay well fatigue of the diaphragm does not commonly impede
below their capacity. For example, in most untrained the ventilatory response. Indirect evidence from pres-
healthy subjects, the pressure generated by inspira- sure recordings suggests that the fatiguing diaphragm
tory muscles during maximum short-term progressive actually reduces its output as a force generator dur-
exercise test is only about 50% of maximum dynamic ing the latter stages of sustained endurance exer-
capacity (Johnson et al., 1992), the oxygen cost of cise and accessory inspiratory and expiratory muscles
breathing approximates 10% of the V̇O2MAX (Aaron become the dominant effectors of a time-dependant
et al., 1992) and diaphragm fatigue does not occur. hyperventilation (Johnson et al., 1992; Babcock et al.,
244 J.A. Dempsey et al. / Respiratory Physiology & Neurobiology 151 (2006) 242–250

2002). So, what are the consequences of a fatigu-


ing diaphragm—other than increasing the reliance on
accessory muscles, which probably add some ineffi-
ciency in terms of an increased oxygen cost of breathing
and some added dyspnea (Ward et al., 1988).
We propose that – as with limb muscle – fatiguing
contractions and accumulation of metabolites in the
inspiratory and expiratory muscles activates unmyle-
nated type IV phrenic afferents (Hill, 2000) (see Fig. 2),
which in turn increases sympathetic vasoconstrictor
activity via a supra-spinal reflex. Studies using repeated
voluntary efforts against resistive loads to the point of
task failure of the inspiratory and/or expiratory mus-
cles in resting humans show a gradual increase in limb
muscle sympathetic nerve activity (MSNA) (St Croix
et al., 2000; Derchak et al., 2002) and a reduction in
vascular conductance and blood flow in the resting limb
Fig. 2. Phrenic nerve stimulation to the point of diaphragm fatigue
(Sheel et al., 2001) (see Fig. 3). Furthermore, in resting
increases the firing rate of type IV metaboreceptors in the diaphragm
and exercising dogs, a transient infusion of lactic acid of anesthetized rats. Activity of type III mechanoreceptors was
specifically into the diaphragm via the phrenic artery reduced (from Hill, 2000).

Fig. 3. Very high work loads and fatigue of the inspiratory muscles achieved via voluntary inspiratory efforts against resistance are required to
gradually increase muscle sympathetic nerve activity and to decrease vascular conductance and blood flow in the resting limb (from St Croix et
al., 2000).
J.A. Dempsey et al. / Respiratory Physiology & Neurobiology 151 (2006) 242–250 245

work rate to exhaustion with randomized trials of three


types, repeated three times each; control, inspiratory
muscle loading (via inspiratory resistors) and respira-
tory muscle unloading (via PAV). Loading decreased
and unloading increased time to exhaustion, averag-
ing ±14–15% (Harms et al., 2000). These alterations
in exercise performance occurred coincidentally with
increases or decreases in the rate of rise of effort per-
ception both for limb discomfort and for dyspnea.
Physiologically, it is the unloading effect that is impor-
tant, because this experiment tests the influence of the
normally occurring work of the respiratory muscles
required to meet the high-sustained ventilatory require-
Fig. 4. Lactic acid transiently infused into the diaphragm via the
phrenic artery (at the arrow) causes a rise in arterial blood pressure ments.
and a reduced hind-limb blood flow and vascular conductance at rest Why does respiratory muscle work affect per-
and mild exercise. These metaboreflex effects from the diaphragm formance? First, the performance effect might be
were prevented via sympathetic blockade (from Rodman et al., 2003). explained by relief of dyspnea perceptions, secondary
to decreased respiratory muscle work. While this effect
reduced blood flow to the limb – both at rest and mild must play a significant role, we postulate that the dele-
exercise – and this effect was prevented via pharmaco- terious effects of respiratory muscle work on perfor-
logic, adrenergic blockade (Rodman et al., 2003) (see mance are also mediated via reduced limb blood flow
Fig. 4). and O2 transport leading to peripheral locomotor mus-
Why is this reflex effect important during exer- cle fatigue.
cise? In healthy subjects if the respiratory muscles are
unloaded using a proportional assist ventilator (PAV)
(Younes, 1992), sufficient to reduce the work of breath- 6. Exercise-induced diaphragmatic fatigue:
ing by 50–60% during heavy intensity cycling exercise, effects on locomotor muscle fatigue
cardiac output is reduced and vascular conductance and
blood flow to the exercising limbs are increased. Con- We quantified the effects of inspiratory muscle
versely, if the work of breathing is artificially increased work on exercise-induced quadriceps muscle fatigue
by adding inspiratory resistance, vascular conductance using supra-maximal stimulation of the femoral nerve
and blood flow to the limb are reduced (Harms et with a double twitch stimulation technique (Yan
al., 1997, 1998). In healthy subjects it takes a sub- et al., 1993; Polkey et al., 1996). Variations in the
stantial increase in the work of breathing to initiate inter-stimulus interval created force: frequency curves
these metaboreflex effects. Thus the effect of unload- for the quadriceps muscle. Within-subject random
ing the respiratory muscles during exercise on vascular variability of twitch force, obtained upon repeat
conductance and blood flow was not observed unless testing both within and between days under resting
exercise intensity was greater than 75% of max (Wetter conditions, was less than 6% (Romer et al., 2005). We
et al., 1999); and in resting subjects blood flow to the performed supra-maximal femoral nerve stimulation
limb was not reduced until inspiratory resistive loads before and immediately following high intensity cycle
were increased sufficiently to cause diaphragm fatigue exercise under conditions of control, loading the
(Sheel et al., 2002). respiratory muscles and unloading. The potential (M
wave) evoked from the quadriceps via supra-maximal
5. Exercise-induced diaphragm fatigue: effects femoral nerve stimulation was unchanged from pre-
on endurance performance exercise baseline to post-exercise, ensuring that equal,
truly supra-maximal stimulation of the quadriceps
Time to exhaustion during cycling at high inten- was achieved before and after exercise. Work rate
sity was determined by having subjects cycle at a fixed and duration and SaO2 were identical across all
246 J.A. Dempsey et al. / Respiratory Physiology & Neurobiology 151 (2006) 242–250

exercise conditions—only the work of breathing was fatigue by about 40% over control conditions—again
changed. when comparisons were made across identical work
We found that exercise, per se, at 90% of maximum rates and exercise durations. These effects of loading
work rate (292 W for 13.2 min) under control condi- and unloading were consistent among all eight sub-
tions, reduced force output of the quadriceps about 30% jects. We found near identical effects of exercise and
across all stimulation frequencies and this fatigue was of superimposed respiratory muscle loads on quadri-
gradually recovered with 70 min of rest following exer- ceps fatigue when testing was repeated on the same
cise (Romer et al., 2006). Following completion of an subjects on different test days. These effects of load-
identical amount and duration of exercise as in con- ing the respiratory muscles on limb fatigue were in the
trol, but with unloading sufficient to reduce the work same direction (but less in magnitude) to the fatigue
of breathing by 50–60%, limb fatigue was significantly caused by the 6–8% arterial O2 desaturation which
less than in control by about one-third (see Fig. 5). normally occurs during high-intensity, constant load
Resistive loading, which increased the work of breath- exercise (Romer et al., 2005). Our current view of the
ing about 80% greater than control, exacerbated limb respiratory muscles metaboreflex and its consequences
are summarized in Fig. 6.
These findings in normal healthy subjects at sea
level likely represent a minimal effect of exercise-
induced respiratory muscle work on limb fatigue, for
two reasons. First we eliminated only a little more
than one-half the normally occurring work of breathing
with PAV. Secondly our loading and unloading effects
were confined to the inspiratory side only. However, we
know that positive intrathoracic pressures during expi-
ration, which occur during heavy intensity exercise in
the face of active expiration and expiratory flow lim-
itation, will reduce stroke volume and cardiac output
(Stark-Leyva et al., 2004). This additional effect may
further compromise limb muscle blood flow—thereby
potentially causing even more muscle fatigue.

7. Conditions under which the effects of


Fig. 5. Summary of effects of increasing and decreasing inspira- respiratory muscle work on limb flow and
tory muscle work on quadriceps fatigue (N = 8) (data from Romer fatigue might be significant
et al., 2006). Percent  twitch force (Qtw ) represents the reduc-
tion in the average quadriceps force output determined across four
stimulation frequencies (1–100 Hz) and compared between base- We would only expect these effects of respiratory
line (pre-exercise) and 2.5 min post exercise. Control vs. respiratory muscle work on limb blood flow and fatigue to occur
muscle unloading (via mechanical ventilation with PAV) effects on during sustained heavy intensity exercise with high
quadriceps fatigue were compared at equal cycle ergometer work ventilatory requirements, sufficient to elicit significant
rates and durations (the duration being determined by the time to
levels of fatigue in the diaphragm and/or accessory
exhaustion under control conditions). Control vs. respiratory muscle
resistive loading effects on quadriceps fatigue were also compared at respiratory muscles. Environmental hypoxia and espe-
equal cycle work rates and durations (the duration being determined cially chronic hypoxic exposure potentiates the hyper-
by the time to exhaustion under loaded conditions). Force output of ventilatory response to exercise and markedly increases
the inspiratory muscles was measured as the time integral of the aver- ventilatory work (Thoden et al., 1969). Thus, we would
age esophageal pressure multiplied by breathing frequency; and for
expect respiratory muscle work to play a more signifi-
the diaphragm, measured as the average trans-diaphragmatic pres-
sure time integral multiplied by breathing frequency. Differences cant role in determining limb O2 transport, limb fatigue
in percent Qtw were significant (* P < 0.01) between control and and exercise performance in hypoxia and especially
unload and control and load (from Romer et al., 2006). during chronic exposure to high altitudes. These effects
J.A. Dempsey et al. / Respiratory Physiology & Neurobiology 151 (2006) 242–250 247

Fig. 6. Schematic of the proposed respiratory muscle metaboreflex and its effects. The metaboreflex is initiated by fatigue of the inspiratory
muscles, mediated supra-spinally via phrenic afferents, leading to sympathetically mediated vasoconstriction of limb locomotor muscle vascu-
latures, exacerbating exercise induced peripheral locomotor muscle fatigue and (via feedback) intensifying effort perceptions and contributing
to limitation of high intensity, endurance exercise performance.

might be offset to some extent if the endurance capac- mal exercise intensities. A rat model of CHF showed
ity and fatigue resistance of the respiratory muscles is elevated blood flow to the diaphragm in mild intensity
enhanced during acclimatization to hypoxia. exercise (Musch, 1993). We have recently observed in
Clinically we might expect the work of the respira- a canine model of heart failure that respiratory muscle
tory muscles to be an especially important determinant unloading (via PAV) increased stroke volume and limb
of limb fatigue and exercise performance in COPD and blood flow even during mild intensity exercise (Miller
in CHF. In COPD patients limb muscles are more fati- et al., 2005a). This effect was attributable in part to a
gable than in healthy subjects (Mador et al., 2003) and reduced after-load on the left ventricle (via less negative
the work of breathing is substantial during exercise. intra-thoracic pressures) and in part to a reduced work
Some of these patients also show a plateau in the limb of breathing relieving the diaphragm metaboreflex.
blood flow during incremental exercise and these same It is important that the cardiovascular influences
patients had a higher ventilatory response (Simon et al., of the work of breathing be tested in these patient
2001). CHF patients typically have both an abnormally populations for two reasons. First it will help unravel
high hyperventilatory response to exercise together some of the complexities of limitations to exercise in
with a reduced stroke volume and cardiac output dur- these complicated clinical conditions which involve
ing exercise and high levels of sympathetic vasocon- both “central” and “peripheral” limitations (see below).
strictor outflow. This combination of factors, i.e., high Secondly successful exercise rehabilitation of these
metabolic demand in the face of reduced O2 trans- patients is extremely difficult because of the very low
port could conceivably cause diaphragm fatigue and exercise tolerance and their extreme symptoms of dys-
compromised limb blood flow even during submaxi- pnea and limb discomfort. Unloading the respiratory
248 J.A. Dempsey et al. / Respiratory Physiology & Neurobiology 151 (2006) 242–250

muscles along with other interventions such as hyper- nervous system to reduce motor output, thereby limit-
oxia, may prove to be an important adjunct to rehabil- ing the velocity and/or force of muscle contraction must
itation therapy, allowing the patient to exercise more be made based on several sources of feedback infor-
vigorously and longer in order to train their extremely mation. Specific peripheral sources of either “reflex
detrained locomotor muscles (O’Donnell et al., 2001). inhibition” of motor output or of heightened percep-
tions of effort or discomfort have not been conclusively
identified—although speculation has favored the car-
8. Fatigue: “central/peripheral”? diac or respiratory musculature or even the brain itself
(Kayser, 2003). Indeed, isolating these mechanisms
In summary, relieving much of the respiratory mus- and assessing their relative importance in the intact
cle work had a positive effect on endurance exercise exercising human or animal would be very difficult.
performance coincident with a significant increase in Our earlier report of a significant correlation between
muscle blood flow and oxygen transport and a reduc- effort perception and exercise performance resulting
tion in locomotor muscle fatigue and reduced percep- from respiratory muscle unloading and loading (Harms
tions of effort—both dyspnea and limb discomfort. et al., 2000) has been interpreted as a cause: effect
We interpret these data to mean that peripheral mus- link—proving that the “brain limits exercise perfor-
cle fatigue played a pivotal role in determining the mance” (Kayser, 2003). However, we suggest that this
observed increase in exercise performance both though interpretation is too narrow; it ignores the reflex con-
its direct effect on limiting muscle force output in nection outlined here between the work of breathing
response to a given motor command and through its leading to respiratory muscle fatigue on the one hand,
feedback effect on increasing sensory input to the CNS and compromised blood flow and O2 transport to the
(see Fig. 7). limbs on the other. In turn, these events lead to a worsen-
Certainly a so-called “central fatigue” or reduced ing of limb muscle fatigue and intensification of effort
motor output to the locomotor muscles during heavy perception. We conclude, therefore, that the onset and
endurance exercise may occur (Gandevia, 2001; progression of (peripheral) locomotor muscle fatigue
Kayser, 2003). This “decision” by the higher central is exacerbated by the respiratory muscle work which
accompanies sustained, heavy intensity exercise; and
postulate that this fatigue is an important dual source
of peripheral and central limitations to exercise perfor-
mance.

9. Several important unknowns remain!

While we believe the essential features of our origi-


nal hypothesis (see Figs. 1 and 6) are supported by the
available evidence, there is much left unexplained in
this proposed respiratory: cardiovascular linkage lead-
ing to limb fatigue with a significant impairment to
exercise performance.
Fig. 7. Schematic of the “peripheral” and “central” fatigue influ-
ences on exercise performance caused by exercise-induced respira- • Exactly how do respiratory and limb locomotor mus-
tory muscle work. The locomotor muscle fatigue (as documented via cle vasculatures compete for the available cardiac
supra-maximal magnetic stimulation of the femoral nerve) is caused output during heavy exercise intensity? When res-
in part by the effect of respiratory muscle work on limb vascular
piratory muscle work is increased and limb flow
resistance and blood flow. In turn, supra-spinal feedback from the
fatiguing locomotor muscles leads to intensification of effort percep- reduced, we presume that the now available “extra”
tions and (perhaps) reflex inhibition, causing reduced motor output flow is diverted to the respiratory muscles—but we
to the locomotor muscles, i.e., “central fatigue”. need to understand if (and why) the respiratory mus-
J.A. Dempsey et al. / Respiratory Physiology & Neurobiology 151 (2006) 242–250 249

cle vasculature would not also undergo vasocon- needs further exploration during whole body exer-
striction in response to the heightened sympathetic cise.
outflow. Alternatively, we also do not know how acti-
vation of the limb muscle metaboreflex influences
blood flow to the inspiratory and expiratory muscles.
Acknowledgements
Thus far, limited information from in vitro studies
of isolated arterioles in diaphragm and limb show
The original work cited in this review was supported
that the diaphragm is less sensitive to vasoconstrictor
by NHLBI and the AHA. We are indebted to Elizabeth
influences but equally sensitive to vasodilator influ-
Aaron, Bruce Johnson, Mark Babcock, Craig Harms,
ences (Aaker and Laughlin, 2002a,b). It is important
Claudette St. Croix, Barbra Morgan, William Sheel and
that in vivo studies at varying exercise intensities
Alex Derchak who each contributed significantly to this
be carried out, contrasting the effects of adrenergic
series of original studies.
stimulation and blockade specifically of the respi-
ratory and locomotor muscle vasculature on their
relative responsiveness.
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