Operation Everest II: neuromuscular performance under conditions of extreme simulated altitude SCOTT ALLEN
H. GARNER, CYMERMAN,
JOHN AND
R. SUTTON, RICHARD CHARLES S. HOUSTON
L. BURSE,
ALAN
McMaster University, Hamilton, Ontario L8N 325, Canada; US Army Research of Environmental Medicine, Natick, Massachusetts 01760-5007; and University of Vermont, Burlington, Vermont 05401 GARNER,~COTTH., JOHN R. SUTTON,RICHARDL. BURSE, ALAN J. MCCOMAS, ALLEN CYMERMAN, AND CHARLESS. HOUSTON.Operation Everest II: neuromuscular performance under conditions of extreme simulated altitude. J. Appl. Physiol. 68(3): 1167-1172, 1990.-The force output of the ankle dorsiflexors was studied during a 40-day simulated ascent of Mt. Everest in a hypobaric chamber;both electrically activated and maximal voluntary contractions (MVCs) were employed. The purposeof this study wasto establishwhether, under conditions of progressivechronic hypoxia, there was a decreasein muscle force output and/or increasedfatigability. We also attempted to identify the main site of any failure, i.e., central nervous system,neuromuscularjunction, or musclefiber. Muscle twitch torque (P,), tetanic torque (PO),MVC torque, and evoked muscle compoundaction potential (M wave) were monitored during 205-sexercise periods in five subjectsat three simulated altitudes (760, 335, and 282 Torr). All three types of torque measurementwere well preserved at the three altitudes. In some subjects, the responsesto stimuli interpolated during repeated MVCs provided evidence of “central” fatigue at altitude. In addition, the rate of fatigue during 20-Hz electrical stimulation was greater (P < 0.01) at altitude and there was increasedfatigability of the twitch (P < 0.025); however, the M wave amplitude was maintained. We conclude that central motor drive becomesmore precariousat altitude and is associatedwith increasedmusclefatigue at low excitation frequencies; the latter is the result, in part, of chronic hypoxia and occurs in the musclefiber interior becauseno impairment in neuromusculartransmissioncould be demonstrated. fatigue; musclecontraction; percutaneousstimulation; tibialis anterior; high altitude
VOLUNTARY EXERCISEcapacity at high altitude
becomes increasingly impaired as barometric pressure falls and O2 availability becomes reduced. These findings are based primarily on studies in which exercise involved large muscle groups and exercise intensity progressed to, or exceeded, maximal aerobic power (25). The results of studies of individual muscles or muscle groups under conditions of hypoxia are contradictory, some showing greater muscle fatigue (11, 17, 24) and others showing no effect (4, 29). Most human studies have been limited to voluntary contractions, and no studies have looked at fatigue during chronic progressive exposure to hypobaric hypoxia. Voluntary muscle strength and endurance are depend-
J. McCOMAS, Institute
ent on the motor command chain from brain to spinal cord, peripheral nerve, neuromuscular junction, and muscle. Impairment at any level can result in a reduction of maximal force generation and increased fatigue. However, pioneering studies by Merton (20) and others (9, 12) suggest that the major site of fatigue during muscle contraction is situated in the muscle fiber and may involve impairment of the excitation-contraction coupling mechanism or failure of the muscle contractile apparatus as a result of failure of its energy supply or through accumulation of a metabolic by-product. During this study, we examined the physiological properties of the tibialis anterior muscle during prolonged exposure to hypobaric hypoxia. We attempted to address three questions: 1) was there deterioration in force output capabilities? 2) was there a change in fatigue resistance to a series of repetitive contractions? and 3) what might cause any impairment of motor function? METHODS Subjects. Nine male subjects (age 21-31 yr) participated in the study. One subject was removed at sea level because of acute bronchitis. Two subjects were removed during the study for transient cerebral hypoxic episodes. Five subjects were available for study at three simulated altitudes. Details of the investigation and the simulated ascent profile have been reported elsewhere (15). Procedures involved in the testing and possible risks were explained to the subjects, whose written consent was obtained. The studies were approved by the Ethics Committees of the US Army and McMaster University. The subjects lived in a hypobaric chamber at the US Army Research Institute of Environmental Medicine at Natick, Massachusetts for 40 days. They were gradually decompressed during this period and reached inspiratory Paz (PIOJ 43 Torr on day 34, a simulated altitude approximately equivalent to the summit of Mount Everest (8,848 m). The chamber was made up of two large rooms, a living area (6.1 X 2.7 m) and a study area (3.7 X 2.7 m) connected by an airlock. The subjects were encouraged to move freely and maintain their usual exercise patterns and exercise equipment was provided (cycle ergometers). The subjects tried to maintain base-line physical activity levels but the level of activity dropped after barometric pressure (PB) 321 Torr (6,700 m, 22,000 ft) (21). 1167
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1168
NEUROMUSCULAR
PERFORMANCE
Two subjects were studied at sea level (760 Torr), at a (PIN, = 60.3), and at 282 Torr (P1oZ = 49.2). The experiments at 335 Torr and 282 Torr were conducted after 24 and 35 days after the base-line (or sea level) experiments. Houston et al. (15) described the ascent profile in detail. During simulated ascent, there was a drop in mean arterial Po2 (Pao,) and PCO~ (Pace,), and arterial pH became alkalemic. The average values at 335 Torr were Pao, 41.7 t 3.3, Pace, 20.0 t 2.8, and pH 7.50 t 0.4 (n = 7). At 282 Torr, the respective values were Pao, 36.6 t 2.2, Pace,, 12.5 t 1.1, and pH 7.53 t 0.3 (n = 6). These physiological changes are described in detail elsewhere (26). Stimulating and recording techniques. The experiments were performed on the ankle dorsiflexor muscles of both legs. Each leg was held in a torque-measuring device similar to that described by Marsh et al. (18). The apparatus held the leg stable while the foot was strapped to a thin plate that rotated coaxially with the ankle joint. A short metal tongue projected perpendicularly from the rear of the foot plate and was held between two horizontal rods attached to metal side plates. When ankle dorsiflexion was attempted, the force developed by the tongue on the rod was detected by strain gauges mounted on the tongue. Subjects were seated during the exercise protocols with the ankle plantar-flexed 20” beyond the neutral position. Torque calibration was established by suspending known weights from a bar clamped to the foot plate just before each of the three study periods. Muscle compound action potentials (M waves) were recorded with a 7-mm silver disc electrode placed over the midbelly portion of the tibialis anterior, and supramaximal stimulation was ensured by increasing the stimulation voltage until the M wave plateaued and then increasing the stimulation intensity by a further 20%. A silver strip served as a reference electrode and was placed around the great toe. A second strip was used as a ground and was attached to the skin -10-15 cm below the knee. The electromyogram (EMG) signal was passed through an amplifier with a band pass of 10 Hz to 1 kHz. The M wave amplitude was used as an indirect measure of neuromuscular transmission and muscle impulse propagation. The muscle fatigue characteristics of one leg of each subject were investigated by intermittent electrical stimulation applied to the common peroneal nerve. The stimulating electrodes comprised two lead plates wrapped in gauze and impregnated with conducting cream; one plate served as the cathode and was placed over the peroneal nerve at the neck of the fibula, whereas the other was placed inferomedially. Base-line twitch recordings were made (for half-relaxation and contraction time measurements) at the start of each session and were followed by tetanic stimulation at 20 Hz for 3 s; after a 2-s rest period, the tetanus was repeated for a total of 36 cycles, thus providing a total exercise period of 205 s. Tetanic torque values were recorded during each cycle; after six cycles, a 5-s rest cycle was allowed, during which a single twitch was obtained (Fig. 1). The other leg was exercised using repeated brief isometric maximal voluntary dorsiflexor contractions
AT ALTITUDE
M-WAVES
SHOWN
ON EMG
TRACE
PB of 335 Torr
single twitch
TORQUE TRACE (N.m)
I I- 1 L
3 SECOND STIMULATED CON TRACTION FIG. 1. Torque trace recordings (bottom) with M wave tracings (top). Example of 20-Hz tetanic torque trace (3 s in duration) followed by a twitch (arrow) given during 5-s rest period.
TORQUE
TRACE
1 cycle - 6x 3 second with
2 second
T WITCH
contractions pauses
Torque traces of 1 of the 6 cycles (6 contractions each) with a 5-s rest period after cycle of contractions during which a single test twitch was administered. Total exercise protocol consisted of 6 cycles (36 contractions with 6 rest periods). FIG.
2.
(MVCs); the sequence resembled the electrical stimulation protocol in that each 3-s contraction was succeeded by a 2-s rest period. A single twitch was elicited after every six cycles and the total protocol consisted of 36 MVCs. The total exercise protocol time for each leg was 205 s (Fig. 2). Central fatigue was studied with the interpolated twitch technique as described previously (1) but with two exceptions. Stimuli were applied to the peroneal nerve rather than directly to the tibialis anterior muscle, and an enlargement of twitch response through the use of a voltage clamp was omitted. Twitches were interpolated during each MVC. An additional procedure was performed at 282 Torr. After a 0.5-h rest period, the electrical stimulation protocol was repeated on four subjects who breathed 100% 02 for 10 min before and throughout the exercise period. This was done to ensure that the events seen during chronic altitude exposure were the result of hypoxia and not to other factors associated with chamber confinement. Failure to improve fatigue with O2 would likely have implicated other factors such as deconditioning. All data were recorded on an FM multichannel tape recorder (Bell and Howell, model UR 3200); measurements were made after playback on a cathode ray oscilloscope (Hewlett-Packard, model 9810 A). Statistics. Significant difference between means was determined by analysis of variance for repeated meas-
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NEUROMUSCULAR
PERFORMANCE
AT
1169
ALTITUDE
1. Muscle performance variables in subjects exposed to progressive chronic hypobaric hypoxia
TABLE
Barometric
n
Pressure, Torr
760
282
52.6t7.0 26.225.9 4.1t1.5
49.7t7.6 27.0k6.2 4.7t1.5
5O.Ok7.3 24.7t7.9 4.9t0.4
74.6t1.2 66.2t16.1
74.4kll.O 64.8t15.8
73.6t10.9 64.0t15.3
5 5
72.0k3.5 81.6klO.l
71.0t7.6 76.0k7.1
72.2k6.8 69.4k8.9
cO.Ol*t
5 5
70.6t13.2 67.4t15.0
62.2t13.8 56.2k7.0
56.8t14.2 56.8t14.2
cO.025"
5
98.0t8.4
5 5 5
Maximal voluntary torque, N m 20-Hz tetanic torque, Nom Twitch torque, Nom Twitch contraction time, ms Twitch half-relaxation time, ms Voluntary fatigue, % 20-Hz tetanic torque fatigue, % Twitch fatigue, % Stimulated leg MVC leg M-wave fatigue, % Stimulated leg l
10 10
101.8k4.9
Values are means t SD. Fatigue values were expressed as (final value/initial 760 Torr at P < 0.05 (simulated altitude effect). “r 282 Torr is significantly altitude effect).
value) different
ures. An orthogonal contrast method was used to look for a simulated altitude effect. Student’s paired t test was used for data with two mean values. The limit for statistical significance was set at P 5 0.05 and values are presented as means t SD.
s 100 z { ‘$/ 90 c, 3 ii
RESULTS
a iI
Chronic altitude exposure did not appear to affect the maximal muscle force-generating capacity, but it did have a mild effect on the susceptibility to fatigue during the exercise protocols. Maximal strength measures (Table 1). The ability of the neuromuscular system to generate contractile force at altitude was determined by comparing maximal twitch torque (P,), 20 Hz tetanic torque (PJ, and MVC (Table 1). There were no significant changes or consistent trends noted in the force output characteristics in any of the three muscle force measures, and this suggests a relative sparing of muscle strength under conditions of chronic hypoxia. Observations during fatigue procedures. During the 205-s period of intermittent voluntary contractions, progressive declines in Pt, P,, and MVC torque were seen at all three altitudes (Figs. 3 and 4). The mean maximal voluntary torque declined to 72% 0 0
0
30
60
90
120
A
760 Torr 335 Torr 282 Torr
150
180
210
Time ts) FIG. 3. Maximal voluntary each point represents mean significant.
P Value
335
contraction torque decay at 3 altitudes; result for 5 subjects. No differences are
NS NS NS NS NS NS
NS
102.6t17.0
NS
x 100. * 335 and 282 Torr
from
335 Torr
at
P
are significantly different from < 0.05 (high vs. moderate simulated
* 0 0 A
P ( 005 760 Torr
335Torr 282Torr
80
t
7o
*
60 1 0 FIG.
4. 20-Hz
11 30 tetanic
II 60 torque
,I 90 decay
I1 120
11 150
at 3 simulated
II 180
I 210 Time (9)
altitudes.
of its initial maximal value after 36 MVCs at sea level. The decay in maximal voluntary torque after 36 contractions at altitude was the same, being 71% at 335 Torr and 72% at 282 Torr (Fig. 3 and Table 1). In contrast, there was an accelerated decline in P, at altitude. Whereas the mean 20-Hz torque decayed at sea level to 81% of its initial value, the values at 335 Torr and 282 Torr were 76% and 69% of initial values, respectively. These differences were highly significant (P < 0.01; Fig. 4 and Table 1). The decline in mean P, was significantly greater at altitude for the twitch evoked during intermittent 20-Hz P, (P c 0.025) but not for the twitch evoked during voluntary exercise (Table 1). However, the twitch measured during the voluntary fatigue protocol was very small in relation to the MVC, so a small decline may have gone undetected. The mean twitch response during stimulation declined to 71% of the initial maximal value at sea level; at 335 and 282 Torr, the declines were to 62 and 57%, respectively (Table 1). At the highest altitude studied (282 Torr), four subjects replicated the 20-Hz tetanic stimulation protocol 30 min after the initial run, breathing 100% 02 by mask for 10 min before and throughout the 205-s protocol. The mean 20-Hz P, without supplemental 02 declined to 68% and was improved to 79% after breathing 100% 02, but this
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1170
NEUROMUSCULAR
PERFORMANCE
change was not significant statistically. The mean twitch evoked during the protocol showed less fatigue when the subjects breathed supplemental O2 (Fig. 5). Without supplemental 02, the twitch declined to 57% of control, but the decay was to 83% with O2 (P < 0.025). A4 ulaue. The M waves associated with the twitches showed no significant change in amplitude during the stimulated contraction run at any of the simulated altitudes studied (Table 1). In some subjects, enlarged amplitude was noted at all three altitudes. Similarly, the single M waves evoked during voluntary exercise did not show any decline in amplitude. Central fatigue. A single stimulus was interpolated during the voluntary contraction fatigue protocol to ensure maximal contraction and to identify incomplete voluntary muscle activation. Unlike the situation at sea level, there were positive interpolated twitch contractions at the highest altitude in two subjects (Fig. 6A). However, all subjects were able to make the interpolated twitch disappear on subsequent contractions when they were urged to make a greater effort (Fig. 6B). Twitch time course. The contraction and half-relaxation times of the twitch responses were documented at all three stimulated altitudes. There was no evidence of a significant change in time course during the study (Table 1).
A
AT ALTITUDE
EMG INTERPOL
TORQUE TRACE (Ah)
ATED
/ 3 seconds
B
1 EMG
? INTERPOLATED
DISCUSSION
STIMULUS
\,
During this JO-day study, the subjects were exposed to at least three conditions that could have had an impact on muscle function: hypoxia, alkalosis, and deconditioning. However, in contrast to the striking respiratory and circulatory adaptations that occur during severe hypoxia (15, 25, 26), the changes in neuromuscular function were mild. Although neuromuscular function in the face of chronic hypoxia has not been studied in detail previously, it is well known that maximal human dynamic work capacity is unfavorably affected by hypoxia, as documented in other Operation Everest II (OEII) exercise protocols (15) and by others (25, 28, 30). Endurance of submaximal work tasks has either not been investigated or its impairment was based on anecdotal evidence. The role of the central and peripheral components of the
* p c.05 li:;iliT?J Room m
Twitch
*
100
air % 02
20 Hz Tetanus
pS( mmHg
) 282
FIG. 5. Fatigue end point reached during 20-Hz tetanic stimulation at 282 Torr. Stippled bars, first stimulated exercise run without supplemental 02; hatched bars, a second stimulated exercise run done at least 30 min later during supplemental O2 (100%) breathing. Values expressed as nercent of control at 205 s.
TORQUE 3 second
TRACE voluntary
(N.m) con traction
FIG. 6. A: bottom, inconsistent voluntary torque with superimposition of small interpolated twitch (arrow). After interpolated stimulus, both torque and raw EMG (top) increased. B: raw EMG tracing (top) with single spike (arrow) corresponding to an interpolated supramaxima1 stimulus. Superimposed stimulus does not result in a torque increment, which signifies presence of full central drive (1).
nervous systems in contributing to this reduced work capacity has not been elucidated. As opposed to other OEII exercise protocols, this study focused on the performance of one group of muscles, the ankle dorsiflexors. The experimental protocol was unlikely to have disturbed the body’s internal milieu significantly in terms of exacerbating deoxygenation or acidosis, although there may have been local effects. In other OEII exercise protocols, a significant worsening of arterial desaturation was noted during exercise (26). We observed greater fatigue of ankle dorsiflexor torque for both electrically activated single twitches and 20-Hz tetanic contractions during repeated contractions under the conditions of chronic altitude exposure. The preservation of neuromuscular transmission, judged by maintenance of the M waves, placed the site of fatigue beyond the sarcolemma; either excitation-contraction uncoupling or failure of the contractile mechanism must have been involved (2, 10). Hypoxia was obviously a significant factor contributing to fatigue at altitude; thus, when supplemental O2 was administered at 282 Torr, significant imnrovement in muscle twitch endurance resulted.
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NEUROMUSCULAR
PERFORMANCE
The relative fatigability of 20-Hz P, during electrically stimulated exercise at simulated altitude, compared with the absence of significant fatigue for repeated MVCs, deserves comment. This discrepancy may reflect a greater susceptibility of the muscles to low-frequency fatigue (10) during hypoxia. Thus the frequency of excitation during 20-Hz stimulation was significantly lower than motor unit firing rates observed in the tibialis anterior in the course of MVCs (30-50 Hz; unpublished observations; Ref. 14). However, there is no obvious reason for the greater decline of the twitch during stimulated, as opposed to voluntary, contractions. The experiments in which maximal stimuli were interpolated during MVCs so as to detect any loss of descending motor drive were informative. Thus, in some subjects, at extreme simulated altitude twitches in response to interpolated stimuli were present initially, suggesting that the central drive had slackened; in such cases, greater effort invariably increased voluntary torque and abolished the elicited twitches. These findings were in contrast to those at sea level and lower simulated altitudes in which interpolated twitch responses were never seen during MVCs of the ankle dorsiflexors (1). We therefore conclude that, at simulated extreme altitude, volitional central motor drive may lose its safety margin for exciting motoneurons. This conclusion would be consistent with such observations as the slowing of fine movements at altitude (27) and the reduction in dynamic work output noted in companion studies (26); the latter used demanding exercise protocols involving large muscle groups for long time periods yet was unable to find evidence of peripheral fatigue (e.g., ATP, creatine phosphate, and glycogen were less reduced, and less lactate accumulated at exhaustion at extreme simulated altitude) (26). It is possible that the rather tenuous voluntary motor drive at altitude is the result not only of cerebral hypoxia but of diminished motor activity in our subjects during the period of the study (13, 22). However, such disuse did not affect either the size and time course of the P, or the P, and MVC torques (3, 6, 7, 22). Thus there was little evidence that deconditioning played a significant role in the function of the peripheral neuromuscular system. Another factor that might have influenced our results was the alkalosis that occurred at altitude. For example, in experiments at sea level, Jones et al. (16) found that alkalosis induced by the ingestion of sodium bicarbonate improved cycling endurance. However, if maximal pedalling force was employed, the effect was not seen (19); these last observations may be more relevant to the present study in which MVCs were used. The results of this study, performed on subjects exposed to progressively more severe chronic hypoxia, have led to the following conclusions: 1) muscle force generation capabilities are preserved; 2) fatigue of Pt and 20Hz P, are greater at altitude; 3) repeated MVCs did not show appreciable fatigue, but the effort required to make contractions was more difficult to sustain; and 4) the suspected major sites of fatigue are the muscle fiber interior and the descending motor drive.
1171
AT ALTITUDE
This paper is part of a series describing a study of acclimatization to hypobaric hypoxia conducted at and with the help of the US Army Research Institute of Environmental Medicine, Natick, MA. Principal investigators were Charles S. Houston, John R. Sutton, and Allen Cymerman. To the many who participated we express our appreciation, especially to the nine subjects who prefer to remain anonymous; their patience and sufferance made the project possible. We are also indebted to Catherine Rushton, Ann Murray, Dr. Digby Sale, and Glenn Shine for secretarial and technical assistance. The views, opinions and/or findings contained in this report are those of the authors and should not be construed as an official Department of the Army position, policy, or decision unless so designated by other official documentation. Human subjects participated in these studies after giving their free and informed voluntary consent. Investigators adhered to AR 70-25 and USAMRDC Regulation 70-25 on use of volunteers in research. Address for reprint requests: S. H. Garner, Chedoke-McMaster Rehabilitation Centre, Box 2000, Station A, Hamilton, Ontario L8N 325, Canada. Received 4 November 1988; accepted in final form 27 October 1989.
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Appl. Physiol. 52: 1113-1118, 1982. 4. BOWIE, W., AND G. R. GUMMING, Sustained handgrip reproducibility: effects of hypoxia. Med. Sci. Sports 3: 24-31, 1971. 5. BURSE, R. L., A. CYMERMAN, AND A. J. YOUNG. Respiratory
response and muscle function during isometric handgrip exercise at high altitude. Aviat. Space Environ. Med. 58: 39-46, 1987. 6. CORLEY, K., N. KOWALCHUK, AND A. J. MCCOMAS. Contrasting effects of suspension on hind limb muscles in the hamster. Exp. Neurol. 85: 102-112, 1984. 7. COYLE, E. F., W. H. MARTIN III, S. A. BLOOMFIELD, 0. H. LOWRY, AND J. 0. HOLLOSZY. Effects of detraining on responses to submaximal exercise. J. Appl. Physiol. 59: 853-859, 1985. 8. CYMERMAN, A., J. T. REEVES, J. R. SUTTON, P. B. ROCK, B. M. GROVES, M. K. MALCONIAN, P. M. YOUNG, P. D. WAGNER, AND C. S. HOUSTON. Operation Everest II: maximal oxygen uptake at extreme altitude. J. Appl. Physiol. 66: 2446-2453, 1989. 9. DAWSON, M. A., D. G. GADIAN, AND D. R. WILKIE. Muscular
fatigue investigated by phosphorus nuclear magnetic resonance. Nature Lond. 274: 861-866, 1978. 10. EDWARDS, R. H. T., D. K. HILL, D.
A. JONES, AND P. A. MERTON. Fatigue of long duration in human skeletal muscle after exercise.
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of pH on cardiorespiratory
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N., G. J. F. HEIGENHAUSER, AND N. L. JONES. on maximal power output and fatigue during shortterm dynamic exercise. J. Appl. Physiol. 55: 225-229, 1983. 20. MERTON, P. A. Voluntary strength and fatigue. J. Physiol. Lond. 19. MCCARTNEY, Effects of pH
123: 553-564,1954. 21. ROSE, M. S., C. S. HOUSTON, C. S. FULCO, G. COANS, J. R. SUTTON, AND A. CYMERMAN. Operation Everest II: nutrition and body composition. J. Appl. Physiol. 65: 2545-2551, 1988. 22. SALE, D. G., A. J. MCCOMAS, J. D. MACDOUGALL, AND A. R. M. UPTON. Neuromuscular adaptation in human thenar muscles following strength training and immobilization. J. Appl. Physiol. 53: 419-424,1982. 23. SPRIET, L. L., M. I. LINDINGER, G. J. F. HEIGENHAUSER, AND N. L. JONES. Effects of alkalosis on skeletal muscle metabolism and performance during exercise. Am. J. Physiol. 251 (Regulatory Integrative Cornp. Physiol. 20): R833-R839, 1986. 24. SUTTON, J. R., K. R. MILLS, A. J. COBLEY, D. A. JONES, AND R. H. T. EDWARDS. The effect of acute hypoxia on muscle fatigue. In: Hypoxia, Exercise and AZtitude, edited by J. R. Sutton, C. S.
Houston, and N. L. Jones. New York: Liss, 1983, p. 478, abstract 40. 25. SUTTON,
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altitude. Annu. Rev. Physiol. 45: 427-437, 1983. 26. SUTTON, J. R., J. T. REEVES, P. D. WAGNER, B. M. GROVES, A. CYMERMAN, M. K. MALCONIAN, P. B. ROCK, P. M. YOUNG, S. D. WALTER, AND C. S. HOUSTON. Operation Everest II: oxygen transport during exercise at extreme simulated altitude. J. Appl. Physiol. 64: 1309-1321,1988. 27. TOWNES, B. D., T. F. HORBEIN, R. B. SCHOENE, F. H. SARNQUIST, AND I. GRANT. Human cerebral function at extreme altitude. In: High Altitude and Man, edited by J. B. West and S. Lahiri. Bethesda, MD: Am. Physiol. Sot., 1984, p. 31-36. 28. WEST, J. B., S. J. BOYER, D. J. GRABER, P. H. HACKETT, K. H. MARET, J. S. MILLEDGE, R. M. PETERS, C. J. Przzo, M. SAMAJA, F. H. SARNQUIST, R. B. SCHOENE, AND R. M. WINSLOW. Maximal exercise at extreme altitudes on Mount Everest. J. Appl. Physiol. 55: 688-698,1983. 29. YOUNG, A., J. WRIGHT, J. KNAPNIK, AND A. CYMERMAN. Skeletal muscle strength during exposure to hypobaric hypoxia. Med. Sci. Sports Exercise 12: 330-335,198O. 30. YOUNG, A. J., A. CYMERMAN, AND R. L. BURSE. The influence of
cardiorespiratory fitness on the decrement in maximal aerobic power at high altitude. Eur. J. Appl. Physiol. Occup. Physiol. 54: 12-15,1985.
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H. GARNER, CYMERMAN,
JOHN AND
R. SUTTON, RICHARD CHARLES S. HOUSTON
L. BURSE,
ALAN
McMaster University, Hamilton, Ontario L8N 325, Canada; US Army Research of Environmental Medicine, Natick, Massachusetts 01760-5007; and University of Vermont, Burlington, Vermont 05401 GARNER,~COTTH., JOHN R. SUTTON,RICHARDL. BURSE, ALAN J. MCCOMAS, ALLEN CYMERMAN, AND CHARLESS. HOUSTON.Operation Everest II: neuromuscular performance under conditions of extreme simulated altitude. J. Appl. Physiol. 68(3): 1167-1172, 1990.-The force output of the ankle dorsiflexors was studied during a 40-day simulated ascent of Mt. Everest in a hypobaric chamber;both electrically activated and maximal voluntary contractions (MVCs) were employed. The purposeof this study wasto establishwhether, under conditions of progressivechronic hypoxia, there was a decreasein muscle force output and/or increasedfatigability. We also attempted to identify the main site of any failure, i.e., central nervous system,neuromuscularjunction, or musclefiber. Muscle twitch torque (P,), tetanic torque (PO),MVC torque, and evoked muscle compoundaction potential (M wave) were monitored during 205-sexercise periods in five subjectsat three simulated altitudes (760, 335, and 282 Torr). All three types of torque measurementwere well preserved at the three altitudes. In some subjects, the responsesto stimuli interpolated during repeated MVCs provided evidence of “central” fatigue at altitude. In addition, the rate of fatigue during 20-Hz electrical stimulation was greater (P < 0.01) at altitude and there was increasedfatigability of the twitch (P < 0.025); however, the M wave amplitude was maintained. We conclude that central motor drive becomesmore precariousat altitude and is associatedwith increasedmusclefatigue at low excitation frequencies; the latter is the result, in part, of chronic hypoxia and occurs in the musclefiber interior becauseno impairment in neuromusculartransmissioncould be demonstrated. fatigue; musclecontraction; percutaneousstimulation; tibialis anterior; high altitude
VOLUNTARY EXERCISEcapacity at high altitude
becomes increasingly impaired as barometric pressure falls and O2 availability becomes reduced. These findings are based primarily on studies in which exercise involved large muscle groups and exercise intensity progressed to, or exceeded, maximal aerobic power (25). The results of studies of individual muscles or muscle groups under conditions of hypoxia are contradictory, some showing greater muscle fatigue (11, 17, 24) and others showing no effect (4, 29). Most human studies have been limited to voluntary contractions, and no studies have looked at fatigue during chronic progressive exposure to hypobaric hypoxia. Voluntary muscle strength and endurance are depend-
J. McCOMAS, Institute
ent on the motor command chain from brain to spinal cord, peripheral nerve, neuromuscular junction, and muscle. Impairment at any level can result in a reduction of maximal force generation and increased fatigue. However, pioneering studies by Merton (20) and others (9, 12) suggest that the major site of fatigue during muscle contraction is situated in the muscle fiber and may involve impairment of the excitation-contraction coupling mechanism or failure of the muscle contractile apparatus as a result of failure of its energy supply or through accumulation of a metabolic by-product. During this study, we examined the physiological properties of the tibialis anterior muscle during prolonged exposure to hypobaric hypoxia. We attempted to address three questions: 1) was there deterioration in force output capabilities? 2) was there a change in fatigue resistance to a series of repetitive contractions? and 3) what might cause any impairment of motor function? METHODS Subjects. Nine male subjects (age 21-31 yr) participated in the study. One subject was removed at sea level because of acute bronchitis. Two subjects were removed during the study for transient cerebral hypoxic episodes. Five subjects were available for study at three simulated altitudes. Details of the investigation and the simulated ascent profile have been reported elsewhere (15). Procedures involved in the testing and possible risks were explained to the subjects, whose written consent was obtained. The studies were approved by the Ethics Committees of the US Army and McMaster University. The subjects lived in a hypobaric chamber at the US Army Research Institute of Environmental Medicine at Natick, Massachusetts for 40 days. They were gradually decompressed during this period and reached inspiratory Paz (PIOJ 43 Torr on day 34, a simulated altitude approximately equivalent to the summit of Mount Everest (8,848 m). The chamber was made up of two large rooms, a living area (6.1 X 2.7 m) and a study area (3.7 X 2.7 m) connected by an airlock. The subjects were encouraged to move freely and maintain their usual exercise patterns and exercise equipment was provided (cycle ergometers). The subjects tried to maintain base-line physical activity levels but the level of activity dropped after barometric pressure (PB) 321 Torr (6,700 m, 22,000 ft) (21). 1167
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1168
NEUROMUSCULAR
PERFORMANCE
Two subjects were studied at sea level (760 Torr), at a (PIN, = 60.3), and at 282 Torr (P1oZ = 49.2). The experiments at 335 Torr and 282 Torr were conducted after 24 and 35 days after the base-line (or sea level) experiments. Houston et al. (15) described the ascent profile in detail. During simulated ascent, there was a drop in mean arterial Po2 (Pao,) and PCO~ (Pace,), and arterial pH became alkalemic. The average values at 335 Torr were Pao, 41.7 t 3.3, Pace, 20.0 t 2.8, and pH 7.50 t 0.4 (n = 7). At 282 Torr, the respective values were Pao, 36.6 t 2.2, Pace,, 12.5 t 1.1, and pH 7.53 t 0.3 (n = 6). These physiological changes are described in detail elsewhere (26). Stimulating and recording techniques. The experiments were performed on the ankle dorsiflexor muscles of both legs. Each leg was held in a torque-measuring device similar to that described by Marsh et al. (18). The apparatus held the leg stable while the foot was strapped to a thin plate that rotated coaxially with the ankle joint. A short metal tongue projected perpendicularly from the rear of the foot plate and was held between two horizontal rods attached to metal side plates. When ankle dorsiflexion was attempted, the force developed by the tongue on the rod was detected by strain gauges mounted on the tongue. Subjects were seated during the exercise protocols with the ankle plantar-flexed 20” beyond the neutral position. Torque calibration was established by suspending known weights from a bar clamped to the foot plate just before each of the three study periods. Muscle compound action potentials (M waves) were recorded with a 7-mm silver disc electrode placed over the midbelly portion of the tibialis anterior, and supramaximal stimulation was ensured by increasing the stimulation voltage until the M wave plateaued and then increasing the stimulation intensity by a further 20%. A silver strip served as a reference electrode and was placed around the great toe. A second strip was used as a ground and was attached to the skin -10-15 cm below the knee. The electromyogram (EMG) signal was passed through an amplifier with a band pass of 10 Hz to 1 kHz. The M wave amplitude was used as an indirect measure of neuromuscular transmission and muscle impulse propagation. The muscle fatigue characteristics of one leg of each subject were investigated by intermittent electrical stimulation applied to the common peroneal nerve. The stimulating electrodes comprised two lead plates wrapped in gauze and impregnated with conducting cream; one plate served as the cathode and was placed over the peroneal nerve at the neck of the fibula, whereas the other was placed inferomedially. Base-line twitch recordings were made (for half-relaxation and contraction time measurements) at the start of each session and were followed by tetanic stimulation at 20 Hz for 3 s; after a 2-s rest period, the tetanus was repeated for a total of 36 cycles, thus providing a total exercise period of 205 s. Tetanic torque values were recorded during each cycle; after six cycles, a 5-s rest cycle was allowed, during which a single twitch was obtained (Fig. 1). The other leg was exercised using repeated brief isometric maximal voluntary dorsiflexor contractions
AT ALTITUDE
M-WAVES
SHOWN
ON EMG
TRACE
PB of 335 Torr
single twitch
TORQUE TRACE (N.m)
I I- 1 L
3 SECOND STIMULATED CON TRACTION FIG. 1. Torque trace recordings (bottom) with M wave tracings (top). Example of 20-Hz tetanic torque trace (3 s in duration) followed by a twitch (arrow) given during 5-s rest period.
TORQUE
TRACE
1 cycle - 6x 3 second with
2 second
T WITCH
contractions pauses
Torque traces of 1 of the 6 cycles (6 contractions each) with a 5-s rest period after cycle of contractions during which a single test twitch was administered. Total exercise protocol consisted of 6 cycles (36 contractions with 6 rest periods). FIG.
2.
(MVCs); the sequence resembled the electrical stimulation protocol in that each 3-s contraction was succeeded by a 2-s rest period. A single twitch was elicited after every six cycles and the total protocol consisted of 36 MVCs. The total exercise protocol time for each leg was 205 s (Fig. 2). Central fatigue was studied with the interpolated twitch technique as described previously (1) but with two exceptions. Stimuli were applied to the peroneal nerve rather than directly to the tibialis anterior muscle, and an enlargement of twitch response through the use of a voltage clamp was omitted. Twitches were interpolated during each MVC. An additional procedure was performed at 282 Torr. After a 0.5-h rest period, the electrical stimulation protocol was repeated on four subjects who breathed 100% 02 for 10 min before and throughout the exercise period. This was done to ensure that the events seen during chronic altitude exposure were the result of hypoxia and not to other factors associated with chamber confinement. Failure to improve fatigue with O2 would likely have implicated other factors such as deconditioning. All data were recorded on an FM multichannel tape recorder (Bell and Howell, model UR 3200); measurements were made after playback on a cathode ray oscilloscope (Hewlett-Packard, model 9810 A). Statistics. Significant difference between means was determined by analysis of variance for repeated meas-
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NEUROMUSCULAR
PERFORMANCE
AT
1169
ALTITUDE
1. Muscle performance variables in subjects exposed to progressive chronic hypobaric hypoxia
TABLE
Barometric
n
Pressure, Torr
760
282
52.6t7.0 26.225.9 4.1t1.5
49.7t7.6 27.0k6.2 4.7t1.5
5O.Ok7.3 24.7t7.9 4.9t0.4
74.6t1.2 66.2t16.1
74.4kll.O 64.8t15.8
73.6t10.9 64.0t15.3
5 5
72.0k3.5 81.6klO.l
71.0t7.6 76.0k7.1
72.2k6.8 69.4k8.9
cO.Ol*t
5 5
70.6t13.2 67.4t15.0
62.2t13.8 56.2k7.0
56.8t14.2 56.8t14.2
cO.025"
5
98.0t8.4
5 5 5
Maximal voluntary torque, N m 20-Hz tetanic torque, Nom Twitch torque, Nom Twitch contraction time, ms Twitch half-relaxation time, ms Voluntary fatigue, % 20-Hz tetanic torque fatigue, % Twitch fatigue, % Stimulated leg MVC leg M-wave fatigue, % Stimulated leg l
10 10
101.8k4.9
Values are means t SD. Fatigue values were expressed as (final value/initial 760 Torr at P < 0.05 (simulated altitude effect). “r 282 Torr is significantly altitude effect).
value) different
ures. An orthogonal contrast method was used to look for a simulated altitude effect. Student’s paired t test was used for data with two mean values. The limit for statistical significance was set at P 5 0.05 and values are presented as means t SD.
s 100 z { ‘$/ 90 c, 3 ii
RESULTS
a iI
Chronic altitude exposure did not appear to affect the maximal muscle force-generating capacity, but it did have a mild effect on the susceptibility to fatigue during the exercise protocols. Maximal strength measures (Table 1). The ability of the neuromuscular system to generate contractile force at altitude was determined by comparing maximal twitch torque (P,), 20 Hz tetanic torque (PJ, and MVC (Table 1). There were no significant changes or consistent trends noted in the force output characteristics in any of the three muscle force measures, and this suggests a relative sparing of muscle strength under conditions of chronic hypoxia. Observations during fatigue procedures. During the 205-s period of intermittent voluntary contractions, progressive declines in Pt, P,, and MVC torque were seen at all three altitudes (Figs. 3 and 4). The mean maximal voluntary torque declined to 72% 0 0
0
30
60
90
120
A
760 Torr 335 Torr 282 Torr
150
180
210
Time ts) FIG. 3. Maximal voluntary each point represents mean significant.
P Value
335
contraction torque decay at 3 altitudes; result for 5 subjects. No differences are
NS NS NS NS NS NS
NS
102.6t17.0
NS
x 100. * 335 and 282 Torr
from
335 Torr
at
P
are significantly different from < 0.05 (high vs. moderate simulated
* 0 0 A
P ( 005 760 Torr
335Torr 282Torr
80
t
7o
*
60 1 0 FIG.
4. 20-Hz
11 30 tetanic
II 60 torque
,I 90 decay
I1 120
11 150
at 3 simulated
II 180
I 210 Time (9)
altitudes.
of its initial maximal value after 36 MVCs at sea level. The decay in maximal voluntary torque after 36 contractions at altitude was the same, being 71% at 335 Torr and 72% at 282 Torr (Fig. 3 and Table 1). In contrast, there was an accelerated decline in P, at altitude. Whereas the mean 20-Hz torque decayed at sea level to 81% of its initial value, the values at 335 Torr and 282 Torr were 76% and 69% of initial values, respectively. These differences were highly significant (P < 0.01; Fig. 4 and Table 1). The decline in mean P, was significantly greater at altitude for the twitch evoked during intermittent 20-Hz P, (P c 0.025) but not for the twitch evoked during voluntary exercise (Table 1). However, the twitch measured during the voluntary fatigue protocol was very small in relation to the MVC, so a small decline may have gone undetected. The mean twitch response during stimulation declined to 71% of the initial maximal value at sea level; at 335 and 282 Torr, the declines were to 62 and 57%, respectively (Table 1). At the highest altitude studied (282 Torr), four subjects replicated the 20-Hz tetanic stimulation protocol 30 min after the initial run, breathing 100% 02 by mask for 10 min before and throughout the 205-s protocol. The mean 20-Hz P, without supplemental 02 declined to 68% and was improved to 79% after breathing 100% 02, but this
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1170
NEUROMUSCULAR
PERFORMANCE
change was not significant statistically. The mean twitch evoked during the protocol showed less fatigue when the subjects breathed supplemental O2 (Fig. 5). Without supplemental 02, the twitch declined to 57% of control, but the decay was to 83% with O2 (P < 0.025). A4 ulaue. The M waves associated with the twitches showed no significant change in amplitude during the stimulated contraction run at any of the simulated altitudes studied (Table 1). In some subjects, enlarged amplitude was noted at all three altitudes. Similarly, the single M waves evoked during voluntary exercise did not show any decline in amplitude. Central fatigue. A single stimulus was interpolated during the voluntary contraction fatigue protocol to ensure maximal contraction and to identify incomplete voluntary muscle activation. Unlike the situation at sea level, there were positive interpolated twitch contractions at the highest altitude in two subjects (Fig. 6A). However, all subjects were able to make the interpolated twitch disappear on subsequent contractions when they were urged to make a greater effort (Fig. 6B). Twitch time course. The contraction and half-relaxation times of the twitch responses were documented at all three stimulated altitudes. There was no evidence of a significant change in time course during the study (Table 1).
A
AT ALTITUDE
EMG INTERPOL
TORQUE TRACE (Ah)
ATED
/ 3 seconds
B
1 EMG
? INTERPOLATED
DISCUSSION
STIMULUS
\,
During this JO-day study, the subjects were exposed to at least three conditions that could have had an impact on muscle function: hypoxia, alkalosis, and deconditioning. However, in contrast to the striking respiratory and circulatory adaptations that occur during severe hypoxia (15, 25, 26), the changes in neuromuscular function were mild. Although neuromuscular function in the face of chronic hypoxia has not been studied in detail previously, it is well known that maximal human dynamic work capacity is unfavorably affected by hypoxia, as documented in other Operation Everest II (OEII) exercise protocols (15) and by others (25, 28, 30). Endurance of submaximal work tasks has either not been investigated or its impairment was based on anecdotal evidence. The role of the central and peripheral components of the
* p c.05 li:;iliT?J Room m
Twitch
*
100
air % 02
20 Hz Tetanus
pS( mmHg
) 282
FIG. 5. Fatigue end point reached during 20-Hz tetanic stimulation at 282 Torr. Stippled bars, first stimulated exercise run without supplemental 02; hatched bars, a second stimulated exercise run done at least 30 min later during supplemental O2 (100%) breathing. Values expressed as nercent of control at 205 s.
TORQUE 3 second
TRACE voluntary
(N.m) con traction
FIG. 6. A: bottom, inconsistent voluntary torque with superimposition of small interpolated twitch (arrow). After interpolated stimulus, both torque and raw EMG (top) increased. B: raw EMG tracing (top) with single spike (arrow) corresponding to an interpolated supramaxima1 stimulus. Superimposed stimulus does not result in a torque increment, which signifies presence of full central drive (1).
nervous systems in contributing to this reduced work capacity has not been elucidated. As opposed to other OEII exercise protocols, this study focused on the performance of one group of muscles, the ankle dorsiflexors. The experimental protocol was unlikely to have disturbed the body’s internal milieu significantly in terms of exacerbating deoxygenation or acidosis, although there may have been local effects. In other OEII exercise protocols, a significant worsening of arterial desaturation was noted during exercise (26). We observed greater fatigue of ankle dorsiflexor torque for both electrically activated single twitches and 20-Hz tetanic contractions during repeated contractions under the conditions of chronic altitude exposure. The preservation of neuromuscular transmission, judged by maintenance of the M waves, placed the site of fatigue beyond the sarcolemma; either excitation-contraction uncoupling or failure of the contractile mechanism must have been involved (2, 10). Hypoxia was obviously a significant factor contributing to fatigue at altitude; thus, when supplemental O2 was administered at 282 Torr, significant imnrovement in muscle twitch endurance resulted.
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NEUROMUSCULAR
PERFORMANCE
The relative fatigability of 20-Hz P, during electrically stimulated exercise at simulated altitude, compared with the absence of significant fatigue for repeated MVCs, deserves comment. This discrepancy may reflect a greater susceptibility of the muscles to low-frequency fatigue (10) during hypoxia. Thus the frequency of excitation during 20-Hz stimulation was significantly lower than motor unit firing rates observed in the tibialis anterior in the course of MVCs (30-50 Hz; unpublished observations; Ref. 14). However, there is no obvious reason for the greater decline of the twitch during stimulated, as opposed to voluntary, contractions. The experiments in which maximal stimuli were interpolated during MVCs so as to detect any loss of descending motor drive were informative. Thus, in some subjects, at extreme simulated altitude twitches in response to interpolated stimuli were present initially, suggesting that the central drive had slackened; in such cases, greater effort invariably increased voluntary torque and abolished the elicited twitches. These findings were in contrast to those at sea level and lower simulated altitudes in which interpolated twitch responses were never seen during MVCs of the ankle dorsiflexors (1). We therefore conclude that, at simulated extreme altitude, volitional central motor drive may lose its safety margin for exciting motoneurons. This conclusion would be consistent with such observations as the slowing of fine movements at altitude (27) and the reduction in dynamic work output noted in companion studies (26); the latter used demanding exercise protocols involving large muscle groups for long time periods yet was unable to find evidence of peripheral fatigue (e.g., ATP, creatine phosphate, and glycogen were less reduced, and less lactate accumulated at exhaustion at extreme simulated altitude) (26). It is possible that the rather tenuous voluntary motor drive at altitude is the result not only of cerebral hypoxia but of diminished motor activity in our subjects during the period of the study (13, 22). However, such disuse did not affect either the size and time course of the P, or the P, and MVC torques (3, 6, 7, 22). Thus there was little evidence that deconditioning played a significant role in the function of the peripheral neuromuscular system. Another factor that might have influenced our results was the alkalosis that occurred at altitude. For example, in experiments at sea level, Jones et al. (16) found that alkalosis induced by the ingestion of sodium bicarbonate improved cycling endurance. However, if maximal pedalling force was employed, the effect was not seen (19); these last observations may be more relevant to the present study in which MVCs were used. The results of this study, performed on subjects exposed to progressively more severe chronic hypoxia, have led to the following conclusions: 1) muscle force generation capabilities are preserved; 2) fatigue of Pt and 20Hz P, are greater at altitude; 3) repeated MVCs did not show appreciable fatigue, but the effort required to make contractions was more difficult to sustain; and 4) the suspected major sites of fatigue are the muscle fiber interior and the descending motor drive.
1171
AT ALTITUDE
This paper is part of a series describing a study of acclimatization to hypobaric hypoxia conducted at and with the help of the US Army Research Institute of Environmental Medicine, Natick, MA. Principal investigators were Charles S. Houston, John R. Sutton, and Allen Cymerman. To the many who participated we express our appreciation, especially to the nine subjects who prefer to remain anonymous; their patience and sufferance made the project possible. We are also indebted to Catherine Rushton, Ann Murray, Dr. Digby Sale, and Glenn Shine for secretarial and technical assistance. The views, opinions and/or findings contained in this report are those of the authors and should not be construed as an official Department of the Army position, policy, or decision unless so designated by other official documentation. Human subjects participated in these studies after giving their free and informed voluntary consent. Investigators adhered to AR 70-25 and USAMRDC Regulation 70-25 on use of volunteers in research. Address for reprint requests: S. H. Garner, Chedoke-McMaster Rehabilitation Centre, Box 2000, Station A, Hamilton, Ontario L8N 325, Canada. Received 4 November 1988; accepted in final form 27 October 1989.
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Appl. Physiol. 52: 1113-1118, 1982. 4. BOWIE, W., AND G. R. GUMMING, Sustained handgrip reproducibility: effects of hypoxia. Med. Sci. Sports 3: 24-31, 1971. 5. BURSE, R. L., A. CYMERMAN, AND A. J. YOUNG. Respiratory
response and muscle function during isometric handgrip exercise at high altitude. Aviat. Space Environ. Med. 58: 39-46, 1987. 6. CORLEY, K., N. KOWALCHUK, AND A. J. MCCOMAS. Contrasting effects of suspension on hind limb muscles in the hamster. Exp. Neurol. 85: 102-112, 1984. 7. COYLE, E. F., W. H. MARTIN III, S. A. BLOOMFIELD, 0. H. LOWRY, AND J. 0. HOLLOSZY. Effects of detraining on responses to submaximal exercise. J. Appl. Physiol. 59: 853-859, 1985. 8. CYMERMAN, A., J. T. REEVES, J. R. SUTTON, P. B. ROCK, B. M. GROVES, M. K. MALCONIAN, P. M. YOUNG, P. D. WAGNER, AND C. S. HOUSTON. Operation Everest II: maximal oxygen uptake at extreme altitude. J. Appl. Physiol. 66: 2446-2453, 1989. 9. DAWSON, M. A., D. G. GADIAN, AND D. R. WILKIE. Muscular
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N., G. J. F. HEIGENHAUSER, AND N. L. JONES. on maximal power output and fatigue during shortterm dynamic exercise. J. Appl. Physiol. 55: 225-229, 1983. 20. MERTON, P. A. Voluntary strength and fatigue. J. Physiol. Lond. 19. MCCARTNEY, Effects of pH
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Houston, and N. L. Jones. New York: Liss, 1983, p. 478, abstract 40. 25. SUTTON,
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cardiorespiratory fitness on the decrement in maximal aerobic power at high altitude. Eur. J. Appl. Physiol. Occup. Physiol. 54: 12-15,1985.
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