Lee M. Romer and Michael I.

Polkey
J Appl Physiol 104:879-888, 2008. First published Dec 20, 2007; doi:10.1152/japplphysiol.01157.2007

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J Appl Physiol 104: 879–888, 2008.
First published December 20, 2007; doi:10.1152/japplphysiol.01157.2007. Invited Review

HIGHLIGHTED TOPIC Fatigue Mechanisms Determining Exercise Performance

Exercise-induced respiratory muscle fatigue: implications for performance

Lee M. Romer1 and Michael I. Polkey2

1
Centre for Sports Medicine and Human Performance, Brunel University, Uxbridge; and 2Respiratory Muscle Laboratory,
Royal Brompton Hospital, and National Heart and Lung Institute, London, United Kingdom

Romer LM, Polkey MI. Exercise-induced respiratory muscle fatigue: implica-

tions for performance. J Appl Physiol 104: 879 – 888, 2008. First published
December 20, 2007; doi:10.1152/japplphysiol.01157.2007.—It is commonly held
that the respiratory system has ample capacity relative to the demand for maximal
O2 and CO2 transport in healthy humans exercising near sea level. However, this
situation may not apply during heavy-intensity, sustained exercise where exercise
may encroach on the capacity of the respiratory system. Nerve stimulation tech-
niques have provided objective evidence that the diaphragm and abdominal mus-

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cles are susceptible to fatigue with heavy, sustained exercise. The fatigue appears
to be due to elevated levels of respiratory muscle work combined with an increased
competition for blood flow with limb locomotor muscles. When respiratory muscles
are prefatigued using voluntary respiratory maneuvers, time to exhaustion during
subsequent exercise is decreased. Partially unloading the respiratory muscles during
heavy exercise using low-density gas mixtures or mechanical ventilation can
prevent exercise-induced diaphragm fatigue and increase exercise time to exhaus-
tion. Collectively, these findings suggest that respiratory muscle fatigue may be
involved in limiting exercise tolerance or that other factors, including alterations in
the sensation of dyspnea or mechanical load, may be important. The major
consequence of respiratory muscle fatigue is an increased sympathetic vasocon-
strictor outflow to working skeletal muscle through a respiratory muscle metabore-
flex, thereby reducing limb blood flow and increasing the severity of exercise-
induced locomotor muscle fatigue. An increase in limb locomotor muscle fatigue
may play a pivotal role in determining exercise tolerance through a direct effect on
muscle force output and a feedback effect on effort perception, causing reduced
motor output to the working limb muscles.
respiratory muscles; exercise; diaphragm; abdominals; magnetic stimulation; metaboreflex

THE PURPOSE OF THIS MINIREVIEW is to address the question of patients with chronic obstructive pulmonary disease (COPD)
whether the respiratory demands of exercise contribute signif- and chronic heart failure (CHF).
icantly toward exercise limitation, either directly through lim-
itations of the respiratory muscle pump or indirectly through EXERCISE DEMANDS ON THE RESPIRATORY MUSCLES
effects on limb blood flow and locomotor muscle fatigue. We
describe the mechanical and metabolic costs of meeting the The primary function of the respiratory control system
ventilatory requirements of exercise. We then ask whether the during moderate exercise is to drive alveolar ventilation in
proportion to metabolic requirements such that arterial blood-
respiratory muscles fatigue with exercise, what factors contrib-
gas tensions and acid-base balance are maintained at or near
ute to any such fatigue, and what the implications of these
resting levels. At work rates that engender a metabolic acido-
factors are for exercise tolerance. Finally, we deal with the
sis, there is the additional challenge of effecting compensatory
potential mechanisms by which respiratory muscle fatigue hyperventilation to minimize the fall of arterial pH and prevent
could compromise exercise tolerance and whether it is possible arterial hypoxemia. In addition to maintaining arterial blood-
to overcome this potential respiratory limitation. Our review gas and acid-base homeostasis, ventilation and breathing pat-
focuses on the healthy young adult exercising near sea level. tern must be regulated precisely so that the work performed by
However, we also consider special circumstances that deter- the respiratory muscles is minimized. In the healthy subject,
mine the balance between metabolic demand and respiratory these ventilatory requirements are readily met because the
system capacity in the highly trained endurance athlete and the respiratory muscles are anatomically suited to the increased
clinical implications for respiratory limitations to exercise in ventilatory demands of exercise, and the neural regulation of
breathing is optimal. The diaphragm, for example, has a high
Address for reprint requests and other correspondence: L. M. Romer, Centre
oxidative capacity, a short capillary-to-mitochondrial diffusion
for Sports Medicine and Human Performance, Brunel Univ., Uxbridge UB8 distance for O2, and a velocity of shortening between that of
3PH, United Kingdom (e-mail: [email protected]). fast-twitch and slow-twitch muscles (91). Furthermore, with
http://www. jap.org 8750-7587/08 $8.00 Copyright © 2008 the American Physiological Society 879
Invited Review
880 RESPIRATORY INFLUENCES ON FATIGUE

progressively increasing exercise, activation of expiratory objectively determined by electrically or magnetically stimu-
muscles, in the absence of expiratory flow limitation, reduces lating the motor nerves to the muscle in question across one or
end-expiratory lung volume (EELV) below resting levels (44), more frequencies. Compared with limb muscles, it is difficult
helping to assist the inspiratory muscles in three ways. First, to objectively assess fatigue of the diaphragm because both the
the reduced EELV enables increases in tidal volume to occur muscle and the motor nerves are relatively inaccessible. Thus
over the most linear portion of the respiratory system pressure- force development across the muscle (i.e., transdiaphragmatic
volume relationship such that respiratory system compliance pressure) is estimated by measuring the pressure difference
remains high (99, 123). Second, the reduced EELV means that between gastric and esophageal pressures induced by stimula-
the diaphragm is lengthened, enabling this muscle to operate tion of both phrenic nerves (9, 90, 97, 110). For the abdominal
near its optimal length for force generation (101, 114). Third, muscles, force output is estimated by measuring the gastric
the reduced EELV allows for storage of elastic energy in the pressure response to magnetic stimulation of the thoracic nerve
chest and abdominal walls during expiration that can be used to roots (61). For nerve stimulation to provide a valid measure of
produce a portion of the work required during the ensuing respiratory muscle fatigue it is important to carefully control
inspiration (5, 35), although it is also possible that inspiration for several potential sources of error, including supramaxi-
is aided in this situation by passive descent of the diaphragm mal stimulation (20, 128), isovolumic conditions (47, 114),
(35). Importantly, accessory respiratory muscles are progres- abdominal compliance (58, 73), and postactivation potenti-
sively recruited with increasing ventilatory demand during ation (71, 143).
exercise, thereby sharing the load needed to support the exer- Application of these nerve stimulation techniques to studies
cise hyperpnea (6). The unique structural characteristics of examining resistive breathing or voluntary hyperpnea has

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respiratory muscles combined with the precise neural regula- shown that fatigue can be induced in the human diaphragm (37,
tion of breathing mean that the capacity of these muscles for 93) and abdominal muscles (61). These techniques have also
pressure generation usually exceeds the demands placed on been used to show that whole body endurance exercise can
them. Thus, in most untrained healthy subjects, the pressures induce fatigue of the diaphragm (11–14, 52, 72) and abdominal
produced by the expiratory muscles during maximal exercise muscles (127, 133). In fit normal subjects exercising to exhaus-
are well within the constraints for effective pressure genera- tion (8 –10 min) at intensities that elicit at least 80 – 85% of
tion, and the pressures produced by the inspiratory muscles are V̇O2max, reductions of 15–30% in the transdiaphragmatic pres-
only 40 – 60% of maximum dynamic capacity (54). Further- sure response to supramaximal stimulation of the phrenic
more, the metabolic requirements of the respiratory muscles nerves were consistently obtained within 10 min after exercise,
are relatively low with the O2 cost of breathing during maximal and transdiaphragmatic pressures did not return to near preex-
exercise averaging only 8 –10% of total body O2 consump- ercise values until 1–2 h postexercise (11–14, 52, 72). Inter-
tion (3). estingly, short-term incremental exercise to exhaustion did not
In contrast, the highly fit endurance athlete working at alter stimulated transdiaphragmatic pressures (64, 106, 134), a
higher metabolic rate and ventilation may meet or exceed the phenomenon probably explained by the fact that exercise
capacity of the respiratory system. As exercise intensity and duration was too short for the cumulative work history of the
ventilation increase, airways undergo dynamic compression diaphragm to reach fatiguing levels (106). This latter finding
during expiration, flow limitation occurs, and EELV is forced suggests not only that exercise intensity is important but also
upward so that flow can be increased further (56). At high that exercise duration plays a role in diaphragm fatigue. More
operational lung volumes the inspiratory muscles have to recent studies have reported postexercise declines of about
overcome the added elastic load presented by the lung and 15–25% in the gastric pressure response to magnetic thoracic
chest wall (85). Furthermore, breathing at a higher lung volume nerve stimulation at work rates eliciting ⬎90% of V̇O2max (127,
means that the inspiratory muscles are shorter, with less force- 133), indicating that whole body exercise can also induce
generating capability (4). Accordingly, highly fit subjects ex- abdominal muscle fatigue.
ercising at maximum can increase expiratory pressures to To date, only changes in respiratory muscle force output
levels that exceed the maximal dynamic pressure at which flow have been assessed using nerve stimulation techniques. How-
becomes limited, and peak dynamic inspiratory muscle pres- ever, other changes in muscle function may occur with a
sures can be elevated to 90% of capacity or greater (54). To reduction in force output, such as a change in the velocity of
meet these ventilatory requirements the respiratory muscles muscle shortening or in the ability to shorten under load. A
require a substantial blood flow and O2 supply. Data in highly major component of the exercise response involves high
fit subjects suggest that up to 16% of the total V̇O2 max and total velocities of muscle shortening (i.e., high flow rates) in addi-
cardiac output is devoted to inspiratory and expiratory muscles tion to increases in force output. Thus future studies are needed
during maximum exercise (3, 40). These indirect estimates to determine the role these factors may play in the loss of
agree closely with those in running equines as measured function associated with fatigue.
directly with radiolabeled microspheres (75, 76).
FACTORS CONTRIBUTING TO EXERCISE-INDUCED
EXERCISE-INDUCED RESPIRATORY MUSCLE FATIGUE RESPIRATORY MUSCLE FATIGUE

Muscle fatigue is defined as “a condition in which there is a The cause of exercise-induced respiratory muscle fatigue is
loss in the capacity for developing force and/or velocity of a due, in part, to the high levels of respiratory muscle work that
muscle, resulting from muscle activity under load and which is must be sustained throughout heavy exercise, as shown by the
reversible by rest” (94). Fatigue is evident from a reduced force finding that diaphragmatic fatigue was prevented when dia-
output relative to prior baseline values, where force output is phragmatic work during exercise was reduced by ⬎50% using
J Appl Physiol • VOL 104 • MARCH 2008 • www.jap.org
 Invited Review
RESPIRATORY INFLUENCES ON FATIGUE 881
a mechanical ventilator (11). However, other factors besides exhaustion or a time-dependent metaboreflex (see also
respiratory muscle work must also be responsible for exercise- Cardiorespiratory interactions).
induced respiratory muscle fatigue, because fatigue did not Another approach to determine whether respiratory muscle
occur when the resting subject mimicked the magnitude and fatigue (or the respiratory load) affects exercise tolerance is to
duration of diaphragmatic work incurred during exercise (13). partially unload the respiratory muscles during exercise by
Indeed, fatigue did not occur until the pressures developed by breathing a low-density gas mixture such as 79% helium-21%
the diaphragm were voluntarily increased twofold greater than O2 (heliox). Heliox decreases the turbulent component of
required during whole body exercise at intensities that caused airflow at high levels of ventilation and may facilitate unload-
exercise-induced diaphragmatic fatigue (13). The probable ing of the respiratory muscles by way of reducing expiratory
explanation for why the fatigue threshold of force production flow limitation and dynamic lung hyperinflation (80). Using
for the diaphragm was so much lower during whole body this approach, time to exhaustion during constant-load exercise
exercise than at rest is that, at rest, the volitional increases in was increased at high work rates (⬎85–90% of V̇O2max) (51,
diaphragmatic work mean that large shares of the total cardiac 98, 141) but not at lower work rates (51). However, heliox does
output are devoted to the diaphragm, whereas during exercise not simply unload the respiratory muscles but may also act by
the diaphragm must compete with locomotor muscles for its improving arterial oxygen saturation through the combined
share of the available cardiac output (39, 40). Less blood flow effect of an increase in alveolar ventilation and a decrease in
to the diaphragm promotes inadequate O2 transport, increasing the alveolar-to-arterial oxygen difference (19).
the likelihood of fatigue. An alternative method of unloading the respiratory muscles
is to use a mechanical ventilator. When a proportional assist

Downloaded from jap.physiology.org on September 24, 2010

Collectively, these findings suggest that the development of
diaphragmatic fatigue with exercise is a function of the rela- ventilator was used to partially unload the inspiratory muscles
tionship between the magnitude of diaphragmatic work and the during prolonged heavy exercise (⬎90% of V̇O2max), time to
adequacy of its blood supply: the less blood flow available, the exhaustion was significantly increased, and the rates of rise of
less diaphragmatic work is required to produce fatigue. In V̇O2 and perceptions of respiratory and limb discomfort during
exercise were reduced (41) (Fig. 1). Not all studies have shown
healthy young adults of varying fitness, an imbalance of
a benefit of mechanical unloading on exercise tolerance (30,
muscle force output versus blood flow or O2 transport avail-
60, 77), but these studies were conducted at relatively lower
ability to the diaphragm that favors fatigue appears to occur
exercise intensities (⬃70 – 80% of V̇O2max) in less-fit subjects.
most consistently when the intensity of prolonged endurance
A potential limitation of this approach to unloading is that the
exercise elicits at least 80 – 85% of V̇O2max (52) or arterial O2
pressures delivered by the ventilator during maximal exercise
saturation drops below ⬃85% (10, 135, 136). can be substantial and hence disruptive to subjects, even after
thorough familiarization (41, 106). Another concern is that,
FUNCTIONAL CONSEQUENCES OF RESPIRATORY with few exceptions (106), a placebo group is rarely incorpo-
MUSCLE FATIGUE rated into the experimental design. Studies without a placebo
Several approaches have been used to determine whether group can be criticized for having weak internal validity and
respiratory muscle fatigue affects exercise tolerance. One such for being vulnerable to the potential influence of subject bias.
A limitation of all unloading studies is that it is difficult to
approach is to prefatigue the respiratory muscles at rest and
determine whether the positive effect of reducing respiratory
observe whether subsequent whole body exercise tolerance is
muscle work on exercise tolerance is attributable to the relief of
impaired. Fatigue of inspiratory or expiratory muscles can be
respiratory muscle fatigue or whether this is simply a percep-
produced using resistive loads, while global respiratory muscle
tual benefit obtained by relieving the discomfort attending high
fatigue can be achieved using voluntary hyperpnea. Prefatigue levels of respiratory muscle work. A further consideration is
studies have shown either a significant decrease (69, 79, 132) that inspiratory muscle unloading creates a less-negative in-
or no change (24, 113, 118) in performance during subsequent trathoracic pressure that, through a reduction in ventricular
heavy exercise. However, a problem with some of these studies preload, reduces stroke volume and cardiac output (40, 89).
is that respiratory muscle fatigue was not assessed (24, 79, 118)
or was not quantified objectively using nerve stimulation tech-
MECHANISMS BY WHICH RESPIRATORY MUSCLE FATIGUE
niques (69, 132). Consequently, some of the studies may have
COULD AFFECT EXERCISE TOLERANCE
failed to induce significant levels of respiratory muscle fatigue
before subsequent exercise or overestimated the normally oc- Ventilation and dyspnea. Respiratory muscle fatigue could
curring level of fatigue in response to whole body exercise. An potentially limit exercise tolerance through an inadequate ven-
additional limitation is that it is impossible to induce prior tilatory response (i.e., relative alveolar hypoventilation), an
fatigue without subjects knowing and, hence, difficult to de- alteration in breathing mechanics, an increased sensation of
termine the contribution of subject expectation to changes in dyspnea, or a combination of these factors. Relative alveolar
exercise tolerance. Another concern is that subjects may hypoventilation would be expected to occur if the respiratory
change their breathing pattern after prior fatigue of the respi- muscles were unable to generate the required pressures or a
ratory muscles (68), such that any change in exercise tolerance tachypneic breathing pattern caused high dead space and,
may be due not only to a change in respiratory muscle fatigue therefore, reduced alveolar ventilation. However, studies that
but also to an increased intensity of dyspnea (67, 82). Last, it have documented exercise-induced respiratory muscle fatigue
may be necessary to leave a sufficient interval between the showed that ventilation was generally appropriate for a given
fatiguing task and the subsequent exercise trial so as to metabolic demand [i.e., end-tidal PCO2 (PETCO2) values less
separate the effects of long-lasting fatigue from general than 40 mmHg and O2 saturation near resting values] (11–14,
J Appl Physiol • VOL 104 • MARCH 2008 • www.jap.org
Invited Review
882 RESPIRATORY INFLUENCES ON FATIGUE

expected to increase sensory input to the central nervous

system and, therefore, increase the intensity of dyspnea. Re-
spiratory muscle fatigue per se may increase the intensity of
dyspnea (31, 125, 126, 138), but this effect appears to be
specific to the accessory respiratory muscles because dia-
phragm fatigue does not increase neural respiratory drive
assessed by diaphragm electromyogram (66), and specific
loading of the diaphragm does not increase the sensation of
inspiratory effort (18, 138). Factors independent of fatigue can
also modify dyspnea and potentially influence exercise toler-
ance. For example, increased tension in the respiratory mus-
cles, alterations in the pattern of tension development (velocity,
frequency, and duty cycle), and functional weakening of respi-
ratory muscles, through a decrease in the operating length of
the muscles or an increase in the velocity of shortening, have
a potent influence on dyspnea (82).
Cardiorespiratory interactions. Perhaps a more likely aspect
of respiratory muscle work limiting exercise tolerance is
through a respiratory muscle fatigue-induced metaboreflex,

Downloaded from jap.physiology.org on September 24, 2010

which increases sympathetic vasoconstrictor outflow and com-
promises perfusion of limb locomotor muscle, thereby limiting
its ability to perform work (Fig. 2). Evidence in animals
indicates that the diaphragm and other inspiratory and expira-
tory muscles, as in limb skeletal muscles, are richly innervated
with metaboreceptors (26). Diaphragm fatigue caused a time-
dependent increase in multiunit activity in small-diameter
phrenic afferents in anesthetized cats (15, 49) and in single-unit
activity in group IV afferents in anesthetized rats (45). Fur-
thermore, when metaboreceptors in the diaphragm or expi-
ratory muscles were stimulated electrically, pharmacologi-
cally, or with local lactic acid infusions, efferent sympa-
thetic nerve activity increased and vascular conductance
decreased in several vascular beds, including those in limb
muscle (48, 96, 102).
In humans, high-intensity voluntary contractions of the in-
Fig. 1. Effects of respiratory muscle unloading via mechanical ventilation on spiratory or expiratory muscles against resistive loads to the
endurance exercise capacity at a work rate requiring ⬃90% of maximal oxygen point of task failure or fatigue caused a time-dependent in-
uptake (V̇O2max) in trained male cyclists (n ⫽ 7). Group mean data are shown
for minutes 1–5 of exercise and at exhaustion. Absolute time to exhaustion
crease in muscle sympathetic nerve activity in the resting leg,
under control conditions averaged 9.1 ⫾ 2.6 min (mean ⫾ SD). Unloading the despite a corresponding increase in systemic blood pressure
normal work of breathing by 50% from control increased time to exhaustion in (22, 120). The gradual increase in muscle sympathetic nerve
76% of trials by 1.3 ⫾ 0.4 min (14 ⫾ 5%). Respiratory muscle unloading activity was accompanied by a significant decrease in limb
caused reductions in oxygen uptake (V̇O2; top) and the rate of rise in vascular conductance and limb blood flow (108, 109). The
perceptions of limb discomfort [leg ratings of perceived exertion (RPE);
middle] and respiratory discomfort (dyspnea; bottom) throughout the duration sympathetic and vascular responses that occur with high-
of exercise. Data are from Harms et al. (41). *Significantly different from intensity dynamic contractions of the respiratory muscles are
control (P ⬍ 0.05). similar to those that occur with fatiguing contractions of the
forearm musculature (108, 120).
During whole body exercise, the situation is more compli-
52, 72, 127). Thus it is unlikely that exercise-induced respira- cated because any increase in muscle blood flow depends on
tory muscle fatigue influences the adequacy of alveolar venti- the opposing effects of strong local vasodilators and sympa-
lation or systemic O2 transport. thetic vasoconstrictor activity. What is still unclear is whether
Exercise-induced diaphragmatic fatigue may affect perfor- the respiratory muscle metaboreflex is sufficiently powerful to
mance by decreasing the relative contribution of the diaphragm override the local vasodilator effects present in locomotor
to total ventilation over time with a requirement for accessory muscles and redistribute blood flow to the respiratory muscle
inspiratory and expiratory muscles to be recruited to deliver vasculature. Data in fit human subjects performing maximal
the progressive hyperventilatory response (6, 12, 13, 52). The cycle exercise indicate that reducing inspiratory muscle work
increasing use of accessory respiratory muscles as exercise using a mechanical ventilator causes vascular conductance and
continues may distort the chest wall (34, 36), reduce the blood flow in the exercising limbs to increase (39). Conversely,
mechanical efficiency of breathing (23, 42) and, hence, in- when the force output of the respiratory muscles was increased
crease the metabolic and blood flow demands of these muscles by adding resistors to the inspirate, limb vascular conductance
(see EXERCISE DEMANDS ON THE RESPIRATORY MUSCLES). The pro- and blood flow were reduced (39). It appears likely that the
gressive recruitment of accessory respiratory muscles would be local reductions in vascular conductance were sympathetically
J Appl Physiol • VOL 104 • MARCH 2008 • www.jap.org
 Invited Review
RESPIRATORY INFLUENCES ON FATIGUE 883

Fig. 2. Schematic of the proposed respiratory muscle

metaboreflex and its effects. The metaboreflex is initi-
ated by fatigue of the respiratory muscles, mediated
supraspinally via group III/IV afferents, leading to sym-
pathetically mediated vasoconstriction of limb locomo-
tor muscle vasculature, exacerbating peripheral fatigue
of working limb muscles and (via feedback) intensify-
ing effort perceptions, thereby contributing to limitation
of heavy-intensity endurance exercise performance.
[Adapted from Dempsey et al. (21).]

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mediated because these changes were inversely correlated with work would be expected to impair limb locomotor muscle
changes in norepinephrine spillover across the working limb function. Indeed, when the inspiratory muscles were partially
(39). In canines exercising at moderate work intensities, a unloaded during heavy cycle exercise using a mechanical
bolus infusion of lactic acid into either the phrenic artery or the ventilator, the postexercise decrease in stimulated quadriceps
deep circumflex iliac artery elicited a transient reduction in force was attenuated by about one-third, and perceptual ratings
limb blood flow and vascular conductance (102). Again, these of limb discomfort were reduced (103). Loading the respiratory
vascular responses appeared to be sympathetically mediated muscles using inspiratory resistors exacerbated the severity of
because they were prevented by pharmacological blockade of quadriceps fatigue by ⬃40% and increased the perceptions of
the adrenergic receptors (102). limb discomfort compared with identical exercise with breath-
Although the evidence appears to implicate a significant role ing unimpeded (Fig. 3). These findings, coupled with those
of fatiguing respiratory muscle work in the sympathetically from a previous study showing a significant relationship be-
mediated vasoconstriction of exercising limb muscle vascula- tween changes in limb discomfort with inspiratory muscle
ture, it is necessary to assert that additional respiratory influ- unloading and improvements in exercise tolerance (41), sug-
ences on sympathetic vasoconstrictor outflow would likely be gest that locomotor muscle fatigue is exacerbated by the
present during whole body exercise. These include an inhibi- respiratory muscle work that accompanies sustained heavy
tory effect of lung stretch (27, 107) and an excitatory effect of exercise. We postulate that this extra fatigue plays a pivotal
carotid chemoreceptor stimulation (115, 122). In addition, we role in determining exercise tolerance both through its direct
assume that the reduction in limb blood flow with fatiguing effect on muscle force output (i.e., peripheral fatigue) and
respiratory muscle work is directed toward the respiratory through its feedback effect on effort perceptions, causing
muscles, but it is unclear whether the respiratory muscle reduced motor output to the working limb muscles (i.e., central
vasculature also vasoconstricts in response to global sympa- fatigue) (Fig. 4).
thetic outflow. Likewise, we do not know how activation of the The effect of inspiratory muscle unloading on exercise-
limb muscle metaboreflex affects blood flow to the inspiratory induced limb muscle fatigue likely underestimated what might
and expiratory muscles. In vitro studies of isolated arterioles be attributed to the total work of breathing (103). The normal
have shown that ␣-adrenergic receptors in the diaphragm are work of breathing was reduced by only about one-half. In
less responsive to vasoconstrictor influences but equally sen- addition, unloading was confined to inspiration, which is im-
sitive to vasodilator influences compared with receptors in the portant because recent evidence in humans indicates that the
limb vasculature (1, 2). Thus, at least theoretically, a global expiratory abdominal muscles are fatigable with heavy endur-
increase in sympathetic activity would result in greater vaso- ance exercise (127, 133) and that fatiguing expiratory muscle
constriction in the locomotor than respiratory muscle vascula- work elicits an increase in vasoconstrictive sympathetic nerve
ture and in turn redirect blood flow to the respiratory muscles. activity in resting limb muscle (22). Data in canines exercising
Clearly, in vivo studies are needed to determine the relative at moderate intensity showed that activation of the respiratory
responsiveness of the respiratory and locomotor muscle vas- muscle metaboreflex from the abdominal expiratory muscles
culatures to vasoconstrictor influences during whole body ex- by way of a bolus infusion of lactic acid into the deep
ercise. circumflex iliac artery caused vasoconstriction in resting and
Locomotor muscle fatigue. Reductions in limb blood flow exercising hindlimb muscle and reduced blood flow a small but
and O2 transport in response to fatiguing respiratory muscle significant amount despite increases in systemic blood pressure
J Appl Physiol • VOL 104 • MARCH 2008 • www.jap.org
Invited Review
884 RESPIRATORY INFLUENCES ON FATIGUE

work of breathing during acute moderate hypoxia (arterial O2

saturation 81%) accounts for at least one-third of the total limb
locomotor muscle fatigue induced by exercise and a significant
part of the hypoxia-induced reduction in exercise tolerance (8).
The effects of augmented respiratory muscle work in acute
hypoxia on limb fatigue and exercise tolerance may be espe-
cially significant in chronic hypoxia during which the hyper-
ventilatory response and work of breathing are greatly magni-
fied (129).
Clinically, respiratory muscle work may play a particularly
important role in determining limb fatigue and hence exercise
tolerance in patients with COPD or CHF. In patients with
COPD, the limb muscles are more fatigable (70) and the O2
cost of breathing is higher (65) compared with healthy control
subjects. In addition, a significant fraction of patients with
severe COPD exhibit a plateau in leg blood flow and leg V̇O2
early during incremental exercise. Patients who exhibit a pla-
teau in leg blood flow have higher levels of ventilation and

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dyspnea at submaximal exercise intensities compared with
Fig. 3. Summary of effects of increasing and decreasing inspiratory muscle
patients who do not exhibit a plateau (111), suggesting that
work on quadriceps muscle fatigue (n ⫽ 8). Percent ⌬twitch force (⌬Qtw) blood flow may be redirected to the respiratory muscles in
represents the reduction in the average quadriceps force output determined patients with the highest work of breathing. Patients with CHF
across 4 stimulation frequencies (1–100 Hz) and compared between baseline also have an elevated ventilatory demand (53), as well as a
(preexercise) and 2.5 min postexercise. Control vs. respiratory muscle unload-
ing (via mechanical ventilation) effects on quadriceps muscle fatigue were blunted cardiac output and an exaggerated sympathetic re-
compared at equal cycle ergometer work rates and durations (the durations sponse to exercise (112). Collectively, these factors could
being determined by the time to exhaustion under control conditions). Control compromise limb blood flow and fatigue, even during sub-
vs. respiratory muscle resistive loading effects on quadriceps muscle fatigue
were also compared at equal cycle work rates and durations (the duration being
maximal exercise. A recent study using a canine model of heart
determined by the time to exhaustion under loaded conditions). Force output of failure showed that unloading the respiratory muscles using a
the inspiratory muscles was measured as the time integral of the average mechanical ventilator increased stroke volume and limb blood
esophageal pressure multiplied by breathing frequency and for the diaphragm flow even during moderate exercise (89). The effect was
was measured as the average transdiaphragmatic pressure time integral mul-
tiplied by breathing frequency. Differences in ⌬Qtw were significant (*P ⬍ attributable to a reduced afterload on the left ventricle by way
0.01) between control and unload, and control and load. Data are from Romer of less negative intrathoracic pressures and to relief of the
et al. (103). [Reproduced with permission from Dempsey et al. (21a). Copy- inspiratory muscle metaboreflex through a reduced work of
right Elsevier 2006.] breathing (89).

(102). Furthermore, expiratory flow limitation and prolonged

expiratory time during heavy exercise often result in positive
intrathoracic pressures that meet or exceed those at which
dynamic compression of the airways occurs (54). Positive
intrathoracic pressures will reduce ventricular transmural pres-
sure, thereby decreasing the rate of ventricular filling during
diastole, and reducing stroke volume and cardiac output (86,
121). Active expiration against positive resistance impedes
femoral venous return, even in the face of an active “muscle
pump” (87, 88). These extra expiratory effects may compro-
mise systemic O2 delivery (7) and render the working limb
musculature even more susceptible to fatigue.
CONDITIONS UNDER WHICH RESPIRATORY MUSCLE WORK
AFFECTS LIMB BLOOD FLOW AND FATIGUE

In health, it appears that the effects of respiratory muscle

work on limb blood flow and fatigue occur during heavy Fig. 4. Schematic of the peripheral and central fatigue influences on exercise
sustained exercise only. Respiratory muscle work had to be tolerance caused by exercise-induced respiratory muscle work. The locomotor
increased to near fatiguing levels for muscle sympathetic nerve muscle fatigue [as documented via supramaximal magnetic stimulation
activity to be increased (22, 120), or for blood flow to be (Supramax Stim) of the femoral nerve] is caused in part by the effect of
decreased in a resting (109) or an exercising limb (39, 59, 102, respiratory muscle work on limb vascular conductance and blood flow. In turn,
supraspinal feedback from the fatiguing locomotor muscles leads to increases
139). Exercise in hypoxia would also be expected to exacerbate in perceptual ratings and perhaps reflex inhibition, causing reduced motor
the effects of respiratory muscle work on limb fatigue and output to the locomotor muscles, i.e., central fatigue. [Reproduced with
exercise tolerance. Recent evidence suggests that the increased permission from Dempsey et al. (21a). Copyright Elsevier 2006.]

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 Invited Review
RESPIRATORY INFLUENCES ON FATIGUE 885
OVERCOMING THE RESPIRATORY nisms by which such training exerts an ergogenic effect on
LIMITATIONS TO EXERCISE exercise performance. The ergogenic effect could be due to
relief of respiratory muscle fatigue (105, 131) or limb muscle
Unloading the respiratory muscles during exercise may be a
fatigue (81), perhaps by attenuation of the respiratory muscle
useful adjunct to the supervised rehabilitation of selected
metaboreflex (142). However, the perceptual benefit obtained
patients with increased work of breathing, dyspnea, or circu-
through relieving the discomfort associated with high levels of
latory limitations. Heliox has been shown to be beneficial in respiratory muscle work may also be responsible for at least
relieving symptoms and improving exercise tolerance in pa- some of the improvement in exercise performance (82).
tients with COPD (63, 100) or CHF (74). Mechanical ventila- Clearly, further studies are needed to better understand the
tion during an acute bout of exercise has also been shown to mechanisms by which respiratory muscle training improves
reduce exertional symptoms and increase exercise tolerance in exercise performance.
patients with COPD (62, 144) or CHF (95). When mechanical
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