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

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

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
Fig. 1. Hypothesis: ventilatory requirements DURING sustained,
high intensity exercise in healthy subjects leads to diaphragm fatigue
and eventually to compromised limb blood flow and fatigue (see text).
The estimate of the fraction of the cardiac output (and V̇O2 ) devoted
to the respiratory muscles during exercise at peak work rate is derived
from measurements of muscle blood flow via microspheres in ponies
(Manohar, 1986), from the oxygen cost of respiratory muscle work in
humans (Aaron et al., 1992) and from the reductions in V̇O2 and CO
observed during respiratory muscle unloading in highly fit humans
at maximal exercise (Harms et al., 1998).
muscles are lengthened and operate near their optimal
length for force generation; (b) tidal volume rises by
encroaching on both inspiratory and expiratory reserve
volumes thereby allowing lung volume changes to
occur over the most linear and mechanically efficient
portion of the pressure:volume relationship. Equally
important, accessory respiratory muscles are progres-
sively recruited with increasing ventilatory demand in
exercise, thereby sharing the load needed to support
exercise hyperpnea.
The results of these extraordinary structural char-
acteristics of the respiratory muscles combined with
the neural control of inspiratory and expiratory mus-
cle function and lung volumes means that – with few
exceptions – pressures generated by the inspiratory
muscles during even heavy intensity exercise stay well
below their capacity. For example, in most untrained
healthy subjects, the pressure generated by inspira-
tory muscles during maximum short-term progressive
exercise test is only about 50% of maximum dynamic
capacity (Johnson et al., 1992), the oxygen cost of
breathing approximates 10% of the V̇O2MAX (Aaron
et al., 1992) and diaphragm fatigue does not occur.
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
high intensity exercise, as shown by the finding that
diaphragmatic fatigue was prevented when diaphrag-
matic work was reduced by using a proportional assist
ventilator (PAV) throughout the exercise (Babcock et
al., 2002). However, the diaphragmatic work, per se,
is not sufficient to explain the diaphragmatic fatigue,
because when the resting subject mimicked (by use of
visual and auditory feedback) the magnitude and dura-
tion of diaphragmatic work incurred during endurance
exercise, fatigue did not occur (Babcock et al., 1995).
In fact, fatigue did not occur until diaphragmatic
work was voluntarily increased two-fold greater than
that required during maximum exercise. Why is the
diaphragm so susceptible to fatigue during exercise?
We think this effect reflects the requirement that the
diaphragm must compete with the locomotor muscles
for the available blood flow during heavy intensity exer-
cise, thereby promoting an inadequate oxygen transport
and fatigue of the diaphragm.
4. Exercise-induced diaphragmatic fatigue:
cardiovascular effects
In prolonged high intensity exercise, hyperventila-
tion usually prevails throughout, demonstrating that
fatigue of the diaphragm does not commonly impede
the ventilatory response. Indirect evidence from pres-
sure recordings suggests that the fatiguing diaphragm
actually reduces its output as a force generator dur-
ing the latter stages of sustained endurance exer-
cise and accessory inspiratory and expiratory muscles
become the dominant effectors of a time-dependant
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
Fig. 4. Lactic acid transiently infused into the diaphragm via the
phrenic artery (at the arrow) causes a rise in arterial blood pressure
and a reduced hind-limb blood flow and vascular conductance at rest
and mild exercise. These metaboreflex effects from the diaphragm
were prevented via sympathetic blockade (from Rodman et al., 2003).
reduced blood flow to the limb – both at rest and mild
exercise – and this effect was prevented via pharmaco-
logic, adrenergic blockade (Rodman et al., 2003) (see
Fig. 4).
Why is this reflex effect important during exer-
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-
ing by 50–60% during heavy intensity cycling exercise,
cardiac output is reduced and vascular conductance and
blood flow to the exercising limbs are increased. Con-
versely, if the work of breathing is artificially increased
by adding inspiratory resistance, vascular conductance
and blood flow to the limb are reduced (Harms et
al., 1997, 1998). In healthy subjects it takes a sub-
stantial increase in the work of breathing to initiate
these metaboreflex effects. Thus the effect of unload-
ing the respiratory muscles during exercise on vascular
conductance and blood flow was not observed unless
exercise intensity was greater than 75% of max (Wetter
et al., 1999); and in resting subjects blood flow to the
limb was not reduced until inspiratory resistive loads
were increased sufficiently to cause diaphragm fatigue
(Sheel et al., 2002).
5. Exercise-induced diaphragm fatigue: effects
on endurance performance
Time to exhaustion during cycling at high inten-
sity was determined by having subjects cycle at a fixed
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-
ments.
Why does respiratory muscle work affect per-
formance? First, the performance effect might be
explained by relief of dyspnea perceptions, secondary
to decreased respiratory muscle work. While this effect
must play a significant role, we postulate that the dele-
terious effects of respiratory muscle work on perfor-
mance are also mediated via reduced limb blood flow
and O2 transport leading to peripheral locomotor mus-
cle fatigue.
6. Exercise-induced diaphragmatic fatigue:
effects on locomotor muscle fatigue
We quantified the effects of inspiratory muscle
work on exercise-induced quadriceps muscle fatigue
using supra-maximal stimulation of the femoral nerve
with a double twitch stimulation technique (Yan
et al., 1993; Polkey et al., 1996). Variations in the
inter-stimulus interval created force: frequency curves
for the quadriceps muscle. Within-subject random
variability of twitch force, obtained upon repeat
testing both within and between days under resting
conditions, was less than 6% (Romer et al., 2005). We
performed supra-maximal femoral nerve stimulation
before and immediately following high intensity cycle
exercise under conditions of control, loading the
respiratory muscles and unloading. The potential (M
wave) evoked from the quadriceps via supra-maximal
femoral nerve stimulation was unchanged from pre-
exercise baseline to post-exercise, ensuring that equal,
truly supra-maximal stimulation of the quadriceps
was achieved before and after exercise. Work rate
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
changed.
We found that exercise, per se, at 90% of maximum
work rate (292 W for 13.2 min) under control condi-
tions, reduced force output of the quadriceps about 30%
across all stimulation frequencies and this fatigue was
gradually recovered with 70 min of rest following exer-
cise (Romer et al., 2006). Following completion of an
identical amount and duration of exercise as in con-
trol, but with unloading sufficient to reduce the work
of breathing by 50–60%, limb fatigue was significantly
less than in control by about one-third (see Fig. 5).
Resistive loading, which increased the work of breath-
ing about 80% greater than control, exacerbated limb
Fig. 5. Summary of effects of increasing and decreasing inspira-
tory muscle work on quadriceps fatigue (N = 8) (data from Romer
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-
line (pre-exercise) and 2.5 min post exercise. Control vs. respiratory
muscle unloading (via mechanical ventilation with PAV) effects on
quadriceps fatigue were compared at equal cycle ergometer work
rates and durations (the duration being determined by the time to
exhaustion under control conditions). Control vs. respiratory muscle
resistive loading effects on quadriceps fatigue were also compared at
equal cycle work rates and durations (the duration being determined
by the time to exhaustion under loaded conditions). Force output of
the inspiratory muscles was measured as the time integral of the aver-
age esophageal pressure multiplied by breathing frequency; and for
the diaphragm, measured as the average trans-diaphragmatic pres-
sure time integral multiplied by breathing frequency. Differences
in percent
Qtw were significant (* P < 0.01) between control and
unload and control and load (from Romer et al., 2006).
fatigue by about 40% over control conditions—again
when comparisons were made across identical work
rates and exercise durations. These effects of loading
and unloading were consistent among all eight sub-
jects. We found near identical effects of exercise and
of superimposed respiratory muscle loads on quadri-
ceps fatigue when testing was repeated on the same
subjects on different test days. These effects of load-
ing the respiratory muscles on limb fatigue were in the
same direction (but less in magnitude) to the fatigue
caused by the 6–8% arterial O2 desaturation which
normally occurs during high-intensity, constant load
exercise (Romer et al., 2005). Our current view of the
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
respiratory muscle work on limb flow and
fatigue might be significant
We would only expect these effects of respiratory
muscle work on limb blood flow and fatigue to occur
during sustained heavy intensity exercise with high
ventilatory requirements, sufficient to elicit significant
levels of fatigue in the diaphragm and/or accessory
respiratory muscles. Environmental hypoxia and espe-
cially chronic hypoxic exposure potentiates the hyper-
ventilatory response to exercise and markedly increases
ventilatory work (Thoden et al., 1969). Thus, we would
expect respiratory muscle work to play a more signifi-
cant role in determining limb O2 transport, limb fatigue
and exercise performance in hypoxia and especially
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-
ity and fatigue resistance of the respiratory muscles is
enhanced during acclimatization to hypoxia.
Clinically we might expect the work of the respira-
tory muscles to be an especially important determinant
of limb fatigue and exercise performance in COPD and
in CHF. In COPD patients limb muscles are more fati-
gable than in healthy subjects (Mador et al., 2003) and
the work of breathing is substantial during exercise.
Some of these patients also show a plateau in the limb
blood flow during incremental exercise and these same
patients had a higher ventilatory response (Simon et al.,
2001). CHF patients typically have both an abnormally
high hyperventilatory response to exercise together
with a reduced stroke volume and cardiac output dur-
ing exercise and high levels of sympathetic vasocon-
strictor outflow. This combination of factors, i.e., high
metabolic demand in the face of reduced O2 trans-
port could conceivably cause diaphragm fatigue and
compromised limb blood flow even during submaxi-
mal exercise intensities. A rat model of CHF showed
elevated blood flow to the diaphragm in mild intensity
exercise (Musch, 1993). We have recently observed in
a canine model of heart failure that respiratory muscle
unloading (via PAV) increased stroke volume and limb
blood flow even during mild intensity exercise (Miller
et al., 2005a). This effect was attributable in part to a
reduced after-load on the left ventricle (via less negative
intra-thoracic pressures) and in part to a reduced work
of breathing relieving the diaphragm metaboreflex.
It is important that the cardiovascular influences
of the work of breathing be tested in these patient
populations for two reasons. First it will help unravel
some of the complexities of limitations to exercise in
these complicated clinical conditions which involve
both “central” and “peripheral” limitations (see below).
Secondly successful exercise rehabilitation of these
patients is extremely difficult because of the very low
exercise tolerance and their extreme symptoms of dys-
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-
oxia, may prove to be an important adjunct to rehabil-
itation therapy, allowing the patient to exercise more
vigorously and longer in order to train their extremely
detrained locomotor muscles (O’Donnell et al., 2001).
8. Fatigue: “central/peripheral”?
In summary, relieving much of the respiratory mus-
cle work had a positive effect on endurance exercise
performance coincident with a significant increase in
muscle blood flow and oxygen transport and a reduc-
tion in locomotor muscle fatigue and reduced percep-
tions of effort—both dyspnea and limb discomfort.
We interpret these data to mean that peripheral mus-
cle fatigue played a pivotal role in determining the
observed increase in exercise performance both though
its direct effect on limiting muscle force output in
response to a given motor command and through its
feedback effect on increasing sensory input to the CNS
(see Fig. 7).
Certainly a so-called “central fatigue” or reduced
motor output to the locomotor muscles during heavy
endurance exercise may occur (Gandevia, 2001;
Kayser, 2003). This “decision” by the higher central
Fig. 7. Schematic of the “peripheral” and “central” fatigue influ-
ences on exercise performance caused by exercise-induced respira-
tory muscle work. The locomotor muscle fatigue (as documented via
supra-maximal magnetic stimulation of the femoral nerve) is caused
in part by the effect of respiratory muscle work on limb vascular
resistance and blood flow. In turn, supra-spinal feedback from the
fatiguing locomotor muscles leads to intensification of effort percep-
tions and (perhaps) reflex inhibition, causing reduced motor output
to the locomotor muscles, i.e., “central fatigue”.
nervous system to reduce motor output, thereby limit-
ing the velocity and/or force of muscle contraction must
be made based on several sources of feedback infor-
mation. Specific peripheral sources of either “reflex
inhibition” of motor output or of heightened percep-
tions of effort or discomfort have not been conclusively
identified—although speculation has favored the car-
diac or respiratory musculature or even the brain itself
(Kayser, 2003). Indeed, isolating these mechanisms
and assessing their relative importance in the intact
exercising human or animal would be very difficult.
Our earlier report of a significant correlation between
effort perception and exercise performance resulting
from respiratory muscle unloading and loading (Harms
et al., 2000) has been interpreted as a cause: effect
link—proving that the “brain limits exercise perfor-
mance” (Kayser, 2003). However, we suggest that this
interpretation is too narrow; it ignores the reflex con-
nection outlined here between the work of breathing
leading to respiratory muscle fatigue on the one hand,
and compromised blood flow and O2 transport to the
limbs on the other. In turn, these events lead to a worsen-
ing of limb muscle fatigue and intensification of effort
perception. We conclude, therefore, that the onset and
progression of (peripheral) locomotor muscle fatigue
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.
• Exactly how do respiratory and limb locomotor mus-
cle vasculatures compete for the available cardiac
output during heavy exercise intensity? When res-
piratory muscle work is increased and limb flow
reduced, we presume that the now available “extra”
flow is diverted to the respiratory muscles—but we
need to understand if (and why) the respiratory mus-
 J.A. Dempsey et al. / Respiratory Physiology & Neurobiology 151 (2006) 242–250
cle vasculature would not also undergo vasocon-
striction in response to the heightened sympathetic
outflow. Alternatively, we also do not know how acti-
vation of the limb muscle metaboreflex influences
blood flow to the inspiratory and expiratory muscles.
Thus far, limited information from in vitro studies
of isolated arterioles in diaphragm and limb show
that the diaphragm is less sensitive to vasoconstrictor
influences but equally sensitive to vasodilator influ-
ences (Aaker and Laughlin, 2002a,b). It is important
that in vivo studies at varying exercise intensities
be carried out, contrasting the effects of adrenergic
stimulation and blockade specifically of the respi-
ratory and locomotor muscle vasculature on their
relative responsiveness.
• What specific mechanism activates the respiratory
muscle metaboreflex sufficiently to increase sym-
pathetic vasoconstrictor activity? This activation
appears to require repeated high intensity contrac-
tions over time, but we have not identified the spe-
cific stimuli nor do we know if this effect represents a
“direct” supra-spinal activation of sympathetic neu-
rons or if this requires sensitization of the baroreflex
(McIlveen et al., 2001).
• The evidence for locomotor muscle fatigue being
influenced by respiratory muscle loading/unloading
is based on changes in the magnitude of force output
of the quadriceps in response to supra-maximal stim-
ulation during early recovery from exercise. While
we believe this to be an appropriate, reproducible
test of limb fatigue which correlates positively with
corresponding changes in oxygen transport and in
performance time, we do not know if this reduction
in force causes the curtailment in performance of a
submaximal exercise task. Further, although there is
much speculation, we know of no direct measures of
so-called “central” fatigue during whole body exer-
cise nor evidence for specific sites of any supposed
reflex inhibition of motor output.
• The ventilatory response to heavy exercise cer-
tainly requires an increased work and metabolic cost
caused by the respiratory muscles whose reflex influ-
ences on limb blood flow we have emphasized in this
review. However, there remains a significant effect
of changes in intra-thoracic and abdominal pressures
during both inspiration and expiration on venous
return from the limbs (Miller et al., 2005b) and on left
ventricular output (Stark-Leyva et al., 2004), which
249
needs further exploration during whole body exer-
cise.
Acknowledgements
The original work cited in this review was supported
by NHLBI and the AHA. We are indebted to Elizabeth
Aaron, Bruce Johnson, Mark Babcock, Craig Harms,
Claudette St. Croix, Barbra Morgan, William Sheel and
Alex Derchak who each contributed significantly to this
series of original studies.
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