Integrative Physiology & Exercise

Respiratory System Determinants of Peripheral

Fatigue and Endurance Performance
JEROME A. DEMPSEY, MARKUS AMANN, LEE M. ROMER, and JORDAN D. MILLER
John Rankin Laboratory of Pulmonary Medicine, University of Wisconsin–Madison, Madison, WI

ABSTRACT
DEMPSEY, J. A., M. AMANN, L. M. ROMER, and J. D. MILLER. Respiratory System Determinants of Peripheral Fatigue and
Endurance Performance. Med. Sci. Sports Exerc., Vol. 40, No. 3, pp. 457–461, 2008. We briefly summarize recent evidence pertaining to
how mechanisms primarily under the control of the respiratory system—namely, arterial oxyhemoglobin desaturation, respiratory muscle

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work and fatigue, and cyclical fluctuations in intrathoracic pressure—may contribute to exercise limitation. Respiratory influences on
cardiac output and on sympathetic vasoconstrictor activity and blood flow distribution are shown to be important determinants of
performance. We also address how a compromised O2 transport exacerbates the rate of development of peripheral muscle fatigue and,
in turn, precipitates central fatigue and exercise limitation. Key Words: ARTERIAL O2 DESATURATION, MUSCLE
METABOREFLEX, INTRATHORACIC PRESSURES, LUNG:CARDIOVASCULAR INTERACTIONS

Note the arterial HbO2 desaturation (mean = j7% SaO2

W
ith few exceptions, in the highly trained endur-
ance athlete (7), the lungs, airways, and respira-
tory muscles of healthy humans are clearly
‘‘overbuilt’’ for the ventilatory and gas-exchange demands
imposed by short-term exercise of any intensity. In this brief
account, we summarize how this scenario may not apply in
heavy-intensity, sustained exercise during which three
mechanisms, in whole or in part under respiratory system
control, may be shown to contribute to performance
limitation.
EXERCISE-INDUCED ARTERIAL
OXYHEMOGLOBIN DESATURATION
Heavy-intensity, sustained exercise causes a time-dependent
arterial oxyhemoglobin (HbO2) desaturation in arterial blood
because of both respiratory and nonrespiratory influences.
Editor’s Note: This paper is an Editor-in-Chief–invited contribution from
ACSM’s conference on Integrative Physiology of Exercise held in Indian-
apolis, Indiana, September 27–30, 2006.
Address for correspondence: Jerome A. Dempsey, Ph.D., University of
Wisconsin–Madison, 4245 MSC, 1300 University Avenue, Madison,
WI 53706; E-mail: jdempsey@wisc.edu.
Submitted for publication June 2007.
Accepted for publication July 2007.
0195-9131/08/4003-0457/0
MEDICINE & SCIENCE IN SPORTS & EXERCISEÒ
Copyright Ó 2008 by the American College of Sports Medicine
DOI: 10.1249/MSS.0b013e31815f8957
below rest, range j5 to j10%) that occurs during a laboratory
simulation of a 5-km bicycle race in fit cyclists (1) (Fig. 1).
The HbO2 desaturation occurs primarily in response to a
rightward shift in the HbO2-dissociation curve because of a
progressive metabolic acidosis and a rise in blood temper-
ature, which occurs to varying extents in all subjects. A
reduced arterial PO2 also contributes in some subjects.
Similar levels of O2 desaturation were achieved during a
constant-load, high-intensity exercise bout to exhaustion (22).
Using a constant–work rate test, we contrasted the time to
exhaustion and the degree of exercise-induced locomotor
muscle fatigue in normoxia versus mild hyperoxia—the latter
with an elevation in FIO2 (0.23–0.29) just sufficient to
maintain the percent HbO2 saturation at resting levels
(~98%). Peripheral fatigue specific only to the quadriceps
muscle was determined by pre- to postexercise changes in
isometric force output in response to supramaximal magnetic
stimulation of the femoral nerve ($Qtw).
Preventing the normally occurring O2 desaturation dur-
ing the constant-load exercise also prevented a significant
fraction of the exercise-induced peripheral fatigue (Fig. 2)
and reduced the rate of rise of perception of limb discomfort
and prolonged exercise time to exhaustion (22). So, the rate
of development of peripheral muscle fatigue and its
subsequent feedback effects on central motor output and
on exercise performance are apparently quite sensitive to
even these seemingly small decrements of 6–10% below
resting levels in HbO2 saturation that are experienced during
heavy-intensity, sustained exercise (22) or time-trial per-
formances (1) in a normoxic environment. This limitation

457

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 FIGURE 2—Effects of preventing exercise-induced arterial HbO2
desaturation on peripheral muscle fatigue as measured by the change
in the force:frequency relationship of the quadriceps in response to
supramaximal magnetic stimulation of the femoral nerve. Both the
control exercise (SaO2 92%) and the exercise in which SaO2 was
prevented from falling FIO2 (iso SaO2 $ 98%) were conducted at
identical work rates (294 W) and for identical amounts of time (13.2
min). Note the significant alleviation of peripheral fatigue achieved by
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preventing the exercise-induced reduction in HbO2 saturation. Figure

reproduced from Romer et al. (22), with permission.

to supramaximal phrenic nerve stimulation, pre- versus post-

exercise (4,5,13). This exercise-induced respiratory muscle
fatigue does not limit the hyperventilatory response through-
out exercise. However, it does trigger a metaboreflex from
the fatiguing diaphragm (12), which in turn causes sympa-
thoexcitation (25) and vasoconstriction (9,10,24) of the
vasculature of the exercising limb, resulting in a reduced
limb blood flow. Accordingly, when a special mechanical
ventilator (28) was used to reduce the work of breathing of
the inspiratory muscles by 40–60%, this prevented exercise-
induced diaphragm fatigue (4) and also reduced the rate of rise
of effort perceptions of limb discomfort throughout the

FIGURE 1—Changes in power output, pH, HbO2 saturation, temper-

ature, PO2, and lactate in arterial blood during the course of a 5-km
time trial conducted on a cycle ergometer. The average time of the trial
was 8.1 T 0.1 min (mean T SD). Data adapted from Amann et al. (1).

becomes progressively more important during heavy-intensity

exercise as SaO2 is further reduced at altitudes of only a few
thousand feet above sea level (1–3,22).

EXERCISE-INDUCED RESPIRATORY
MUSCLE WORK
A progressive, time- and intensity-dependent hyperventila-
tion occurs during sustained high-intensity exercise, as shown
for the 5-km time trial in Figure 3 (1). This ventilatory
response requires the progressive recruitment of inspiratory
and expiratory muscles, and if the exercise intensity exceeds
80% of the maximum, significant diaphragm and expiratory FIGURE 3—Progressive, time-dependent hyperventilation occurring
throughout the 5-km cycling time trial. Changes in arterial blood pH
muscle fatigue will occur (13,27). Diaphragm fatigue is and PaO2 accompanying the time trial were shown in Figure 1. Data
quantified by a reduced diaphragm force output in response adapted from Amann et al. (1).

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FIGURE 4—Effects of reducing the work of the inspiratory muscles
FIGURE 6—Schema summarizing the effects of the ventilatory
response to high-intensity, sustained exercise on exercise performance.
In health, very-high-intensity exercise is required to elicit this series of
events, whereas sustained submaximal exercise may be sufficient during
exercise in hypoxic environments or in patients with CHF or COPD.

using a proportional assist mechanical ventilator during exercise to
exhaustion on the force:frequency output of the quadriceps muscle,
pre- versus postexercise. The work rate (292 W) and the average time
of exercise (13.2 min) were identical in the control and unloaded
conditions. Note the reduction in exercise-induced quadriceps fatigue
accomplished by reducing the work of the inspiratory muscles by 40–
60%. Figure reproduced from Romer et al. (23), with permission. Also
see the schema in Figure 6.
exercise. Exercise performance time was increased with
unloading by 14 T 4% (11). Subsequent studies (23) have
shown that reducing the work of breathing during high-
intensity exercise prevented a significant portion of the
exercise-induced quadriceps fatigue (Fig. 4)—an effect that is
likely related to preventing the respiratory muscle metaboreflex
effect on reducing limb blood flow (see above). Exercise in
hypoxic environments intensifies the hyperventilatory
response, the work of breathing and diaphragm fatigue—
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accordingly, the work of the respiratory muscles is likely to
have an even more prominent influence on the development
of peripheral locomotor muscle fatigue and exercise
performance at high altitudes.
So, both exercise-induced arterial HbO2 desaturation and
fatiguing levels of respiratory muscle work compromise O2
transport to working limbs—the former by reducing arterial
O2 content, and the latter by triggering vasoconstriction and
reducing limb blood flow.
PERIPHERAL FATIGUEYCENTRAL FATIGUE
We have documented the effects of arterial O2 content
(CaO2) and respiratory muscle work on peripheral locomotor

FIGURE 5—The effects of progressive increases in work rate on inspiratory and expiratory intrapleural pressures in subjects of varying age and
exercise capacity and in COPD patients. Pcapi refers to the maximum pressures that the inspiratory muscles are capable of generating at the muscle
lengths and velocity of shortening achieved during exercise. Pmaxe represents the pressures at any given lung volume at which the airways will close
and expiratory flow rate is no longer effort dependent. Note that in these examples, the inspiratory intrathoracic pressures generated are within 10%
of maximum capacity, and the expiratory pressures generated often exceed the critical closing pressure of the airway. The effects on cardiac output
generated by these intrathoracic pressures are discussed in the text. Data adapted from Johnson et al. (14,15). Also see the schema in Figure 6.

RESPIRATORY LIMITATIONS Medicine & Science in Sports & Exercised 459

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 muscle fatigue, and we suggest that, in turn, this contributes to
exercise performance limitation. Indeed, significant local
fatigue per se would be expected to compromise force output
of the locomotor muscles in response to a given motor
command. More importantly, peripheral fatigue will impact,
via neural feedback, cortical and/or subcortical perceptions of
muscular effort and, thereby, influence central motor output to
the limbs. We have recently shown that varying FIO2 and
CaO2 from hypoxia to hyperoxia during a 5-km cycling time
trial caused marked O2-transport–dependent changes in
central motor output, power output, and performance time,
but at the point of exhaustion, a nearly identical degree of
peripheral muscle fatigue had occurred (1). These correlative
findings support the postulate that during high-intensity exer-
cise, a critical level of peripheral fatigue is eventually
achieved, which exceeds a threshold of sensory input leading
via feedback to ‘‘central fatigue’’ or reduced central motor
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output and performance limitation (8). A follow-up exper-
imental approach used a fixed work rate to task failure in
normoxia and in moderate and severe hypoxia, with
subsequent reoxygenation via increased FIO2 and an attempt
to continue exercise (3). These findings demonstrate that exer-
cise could not be continued on reoxygenation (at the point of
task failure) if the critical threshold for peripheral fatigue (see
above) was achieved.
Some have argued that it is the ‘‘brain’’—not metabolically
driven changes in the periphery—that determines exercise
performance (16,21). We believe these claims miss the point!
That is, all would agree that the ‘‘decision’’ to reduce power
output during exercise clearly involves motor and higher
areas of the CNS—that is, so-called ‘‘central fatigue’’—and
is obviously important in determining performance! The real
mystery deserving consideration here is the need to identify
those sources of input that trigger these ‘‘decisions’’ to reduce
central motor output (8). We believe the correlative evidence
to date is consistent with a significant role for peripheral
muscle fatigue in this ‘‘decision-making’’ process. We presume
these proposed effects of peripheral fatigue on central motor
output are moderated via established muscle metaboreceptors
and supraspinal neural feedback pathways—but this has not
yet been tested experimentally. We also emphasize that there
are findings to support ‘‘direct’’ effects of exercise per se on
brain metabolism (6) and central fatigue. Furthermore,
hypoxemia, if sufficiently severe (G 75% SaO2), will inhibit
central motor input and limit performance, even in the
absence of substantial levels of peripheral muscle fatigue (3)
or of intact neural feedback from the working limbs (17). We
clearly need more imaginative experiments to sort out the
relative influences of peripheral and central inputs on effort
perceptions, central motor output, and performance limitation.
EXERCISE-INDUCED INSPIRATORY AND
EXPIRATORY INTRATHORACIC PRESSURES
The ventilatory response to heavy-intensity exercise re-
quires substantial recruitment of both inspiratory and expi-
460 Official Journal of the American College of Sports Medicine
Copyright @ 2008 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
ratory muscles and associated augmentation of negative and
positive intrathoracic pressures (Fig. 5). In the presence of
expiratory flow limitation and mild hyperinflation in the
highly trained young and old subjects, these inspiratory pres-
sures may approach 95% of the maximum dynamic pressure
available to the inspiratory muscles (14,15). Furthermore,
with active expiration, pressures often meet and exceed those
at which dynamic compression of airways occurs. The heart
and great vessels are, of course, exposed to these substantial
oscillatory pressures.
Recent work in exercising humans and animals using
mechanical ventilation to reduce inspiratory negative pres-
sure and threshold loads to add expiratory pressure have
revealed significant effects of these pressures on venous
return, stroke volume, and cardiac output during exercise.
For example, in the healthy subject, using a pressure sup-
port ventilator to reduce inspiratory pressure negativity reduces
ventricular ‘‘preload’’ and reduces stroke volume and cardiac
output in the steady state of light- and heavy-intensity exercise
(10,20). So, the negative inspiratory intrathoracic pressure
normally occurring in heavy-intensity exercise has a signifi-
cant (~7–10%) contribution to the increase in end-diastolic
volume and, therefore, to stroke volume and cardiac output.
On the other hand, positive intrathoracic pressures during
expiration—especially in the face of expiratory flow limitation
and prolonged expiratory time (Figs. 5 and 6)—will reduce
ventricular transmural pressure, thereby decreasing the rate of
ventricular filling during diastole and reducing stroke volume
and cardiac output (18,26). Active expiration with positive
expiratory pressures in semirecumbent humans engaging in
plantar flexion exercise was also shown to impede femoral
venous return—even in the face of an active ‘‘muscle pump’’
(19). The use of flow probes on the ascending aorta, allowing
beat-by-beat measurement of cardiac output in the chronically
instrumented exercising dog, shows these mechanical effects
of intrathoracic pressure changes to occur within a few beats
of the imposed pressure change (18,20).
These recent findings in the healthy animal and human
clearly show a significant facilatory effect on cardiac output
from the effects on ventricular preload imposed by inspi-
ratory negative pressures and a substantial limitation on stroke
volume imposed by the effects on ventricular afterload pre-
sented by positive expiratory pressure. Improved methods of
cardiac imaging during whole-body exercise are now required
to determine the detailed mechanisms underlying these
complex respiratory–cardiac interactive effects.
SUMMARY
The physiologic factors that limit endurance exercise
performance are complex and multifacted. They will differ
depending on the duration and intensity of the exercise. We
have briefly outlined how three mechanisms determined in
whole or in part by the respiratory system—namely, arterial
HbO2 desaturation, respiratory muscle work, and inspiratory
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and expiratory intrathoracic pressures—are significant deter-
minants of CaO2 and/or blood flow and its distribution during
exercise in health. Their contribution to exercise limitation is
significant, but likely to be relatively small, in the healthy
subject exercising at sea level. These respiratory limitations
are likely to gain in importance as fitness level rises. They will
also gain in relative importance and are likely to play a
significant limiting role even at submaximal exercise inten-
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Copyright @ 2008 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
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