With few exceptions, in the highly trained endurance athlete (7), the lungs, airways, and respiratory 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. Note the arterial HbO2 desaturation (mean = −7% SaO2 below rest, range −5 to −10%) 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 temperature, 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 (ΔQtw).
Preventing the normally occurring O2 desaturation during 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 performances (1) in a normoxic environment. This limitation 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 hyperventilation 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 muscle fatigue will occur (13,27). Diaphragm fatigue is quantified by a reduced diaphragm force output in response to supramaximal phrenic nerve stimulation, pre- versus postexercise (4,5,13). This exercise-induced respiratory muscle fatigue does not limit the hyperventilatory response throughout exercise. However, it does trigger a metaboreflex from the fatiguing diaphragm (12), which in turn causes sympathoexcitation (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 exercise. Exercise performance time was increased with unloading by 14 ± 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-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 FATIGUE→CENTRAL FATIGUE
We have documented the effects of arterial O2 content (CaO2) and respiratory muscle work on peripheral locomotor 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 exercise, 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 output and performance limitation (8). A follow-up experimental 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 exercise 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 (< 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 requires substantial recruitment of both inspiratory and expiratory 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 pressures 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 pressure 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 support 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 significant (~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 inspiratory negative pressures and a substantial limitation on stroke volume imposed by the effects on ventricular afterload presented 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.
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 and expiratory intrathoracic pressures-are significant determinants 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 intensities in the hypoxic environments of high altitude and in patients with COPD and CHF.
The original research from the author's laboratory reported herein was supported by NHLBI and the American Heart Association. The authors are indebted to Anthony Jacques and Ben Dempsey for manuscript preparation, and to colleagues Bruce Johnson, Kurt Saupe, Mark Babcock, Curtis Smith, Craig Harms, Steve McClaran, Tom Wetter, Josh Rodman, Claudette St. Croix, Alex Derchack, and Barbara Morgan, who contributed original data to this topic.
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