Operation Everest II: metabolic and hormonal responses to incremental exercise to exhaustion.

Operation Everest II: metabolic and hormonal to incremental exercise to exhaustion

responses

PATRICIA M. YOUNG, JOHN R. SUTTON, HOWARD J. GREEN, JOHN T. REEVES, PAUL B. ROCK, CHARLES S. HOUSTON, AND ALLEN CYMERMAN Altitude Physiology and Medicine Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts 01760; Department of Medicine, McMaster University, Hamilton, Ontario L8N 325; Department of Kinesiology, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada; Department of Medicine, University of Colorado Medical Center, Denver, Colorado 80262; and Department of Medicine, University of Vermont, Burlington, Vermont 05401

YOUNG,~ATRICIAM., JOHNR. SUTTON,HOWARDJ. GREEN, JOHNT. REEVES,PAULB.ROCK,CHARLESS.HOUSTON,AND ALLEN CYMERMAN. Operation Everest II: metabolic and hormonal responses to incremental exercise to exhaustion. J. Appl. Physiol. 73(6): 2574-2579,1992.-The reasonsfor the reduced exercise capacities observed at high altitudes are not completely known. Substrate availability or accumulations of lactate and ammonium could have significant roles. As part of Operation Everest II, peak oxygen uptakes were determined in five normal male volunteers with use of progressively increasing cycling work loads at ambient barometric pressuresof 760, 380, and 282 Torr. Decrementsfrom sealevel (SL) to 380 and 282 Torr occurred in peak power output (19 and 47%), time to exhaustion (19 and 48%), and oxygen uptake (41 and 61%), respectively. Arterial saturations after exhaustive exercise were decreasedto 63%at 380Torr and 39% at 282Torr. At 380 and 282 Torr, postexercise plasma concentrations of glucose and free fatty acidswere not increased,whereasplasma glycerol concentrations were decreasedrelative to SL (145-t 24 ,uM at 380 Torr and 77 t IO FM at 282 Torr vs. 213 t 24 PM at SL). Preexercise plasma insulin concentrations were elevated at both 380 and 282 Torr (87 t 16pM at 380 Torr and 85 & 18pM at 282 Torr vs. 41 t 30 pM at SL). In general, postexercise concentrations of plasmacatecholamineswere decreasedat altitude comparedwith SL. Preexercise lactate and ammonium concentrations were not different at any simulated altitude. From these data neither substrate availability nor metabolic product accumulation limited exercisecapacity at extreme simulated altitude. altitude; plasmaammonium;blood lactate; insulin; norepinephrine; epinephrine; plasma catecholamines;exercise endurance ON ASCENT to high altitude,

the lowland resident experiences a number of physiological and biochemical responses in an attempt to compensate for the decrease in ambient PO,. Despite these alterations, with ascent to high altitude, the capacity for exercise decreases (7,30). With acclimatization to 4,300 m altitude, alterations occur in energy substrate utilization for steady-state exercise (29, 31). For example, with cycling exercise at 75% maximal oxygen uptake (VOWmax), decreased blood lactate accumulation was accompanied by a sparing of muscle glycogen with an apparent enhanced utilization of free fatty acids for energy (29). Also, when steady-state

exercise was performed at sea level and after acute (t < 24 h) and chronic (t = 13 days) residence at 4,300 m altitude, only acclimatized subjects had less blood lactate and ammonium accumulation (3 1). Thus acclimatization to high altitude involves numerous interrelated physiological and biochemical responses that lead to improved performance. Although much is known about human performance with exposure and acclimatization to moderate altitudes (7,30), little has been reported regarding blood and muscle concentrations of key substrates and metabolites at extreme altitudes (32). During the conduct of Operation Everest II (13), we examined the effect of gradual simulated ascent over the course of 40 days to an altitude equivalent to that of Mt. Everest (8,848 m). This portion of that study focuses on identification of metabolic factors that may limit performance during exhaustive exercise at extreme altitude. MATERIALS AND METHODS

During the 40-day course of Operation Everest II, five male test subjects (21-31 yr old) were exposed to decreasing ambient pressures from sea level (760 Torr) to 240 Torr (8,848 m)‘ The study was conducted in the hypobaric chamber at the US Army Research Institute of Environmental Medicine in Natick, MA (50 m). Complete details of Operation Everest II were published elsewhere (13). Additional physiological measurements conducted during the course of Operation Everest II are also reported elsewhere (5, 11, 20, 23, 24). Of the initial eight test subjects, two were unable to complete the study, and one did not perform cycling exercise to exhaustion at the highest altitude. Data from these subjects are not included in this study. Lactate and ammonium data were obtained duringprogressive exercise in the initial sea level phase that consisted of a 7-day baseline control period preceding hypobaric exposure on days 13 and 14 of exposure to hypobaric hypoxia at 380 Torr (5,450 m) and on day 33 at 282 Torr (7,615 m). Hypobaric chamber pressures were lowered in 2- to 4-Torr increments during the early morning hours. Subjects remained at the 282 Torr level for ~24 h

2574 Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (137.154.019.149) on January 12, 2019.

EXHAUSTIVE

EXERCISE

before testing was begun. They slept at 314 Torr (6,880 m) the previous night. Five subjects completed an incremental exhaustive cycling exercise protocol in which the work load was increased by 30 W/min. Subjects cycled at 60 revolutions/ min on a cycle ergometer (Monarch) and were paced with an electronic metronome while an observer counted Pe-. da1 revolutions to ensure uniform exercise intensity. Initially, subjects pedaled for 3 min with no load and continued pedaling as the work load was increased by 30-W increments each minute until exhaustion. Variables measured at rest and during each exercise bout included continuous monitoring of heart rate from a precordial lead (model 200 eight-channel recorder, Gould), 0, saturation from an ear oximeter (model 47201-A, HewlettPackard), minute ventilation from a dry gas meter (model CD-4, Parkinson-Cowan), and mixed expired 0, and CO, concentrations (models 1100 A and B, Perkin Elmer mass spectrometer). Ratings of perceived exertion (RPE) (1) for leg and breathing effort were obtained from each subject at the beginning of the each exercise bout at 1-min intervals throughout exercise and at the end of exercise. Pre- and postexercise biopsy samples were obtained from the vastus lateralis, and the results from analyses of these samples are reported elsewhere (9, 10). Thirty minutes before exercise, an l&gauge flexible catheter was placed in a branch of the cephalic vein on the dorsal aspect of the hand of each subject and kept patent by slow infusion of 0.9% saline. Immediately before and after exercise, and after 5- and 15-min recovery periods, blood was collected in EDTA and stored on ice. When exercise was performed under hypobaric conditions, blood samples were transferred from the chamber to the laboratory through an airlock within 5 min of collection. An aliquot of blood was prepared immediately and an .alyzed for lactate concentration with use of an enzymatic autoanalyzer (Kontron Medical, Grand Rapids, MI). Hematologic measurements were performed using a Coulter counter (model S880, Hialeah, FL). For analysis of blood glucagon concentration, samples were collected in ethylene-bis(oxyethylene-nitrile)tetraacetic acid with aprotinin (Sigma Chemical, St. Louis, MO), a protease inhibitor. The remainder of the blood was centrifuged at 4*C. The plasma was divided into separate aliquots and placed in liquid nitrogen (- 196OC) until analyzed. Plasma ammonium concentration was determined with a commercial enzymatic assay kit (Sigma Chemical). A quality control (QC) plasma sample that was collected and stored under identical conditions as the test subjects’ plasma samples was assayed with samples from each subject. The coefficient of variation for the ammonium QC samples (mean 105.5 t 0.7 PM, n = 8) was 5.2%. Plasma concentrations of hormones (insulin, growth hormone, glucagon, epinephrine, and norepinephrine) and metabolites [glucose, glycerol, triglyceride, and plasma free fatty acid (FFA)] were quantified as described previously (32). With each analysis, appropriate standard curves and QC plasma samples were assayed. All samples from each subject were analyzed in triplicate at the same time to avoid interassay variation.

AT

ALTITUDE

2575

Data were analyzed using a three-way analysis of variance by a BMDP statistical program (P4V). Blood lactate and ammonium data were subjected to analysis of covariance using a BMDP statistical program (P2V). A Newman-Keuls multiple range critical difference test was used where appropriate to identify significant differences between means. Statistical significance was accepted at P < 0.05. All data are expressed as means t SE. RESULTS

Exhaustive exercise. When compared with 760 Torr (Table I), endurance time decreased by 19.5% at 380 Torr and 48.3% at 282 Torr (P < 0.01). Endurance time at 282 Torr was reduced 35.8% when compared with 380 Torr (P < 0.01). The final power output (Table l), a function of endurance time, was reduced in a similar manner. The oxygen uptake’(v~,) during the last 2 min of each exercise bout is shown in Table 1. When compared with 760 Torr, the peak VO, was decreased by 41.5% at 380 Torr and 61.0% at 282 Torr (P < 0.01). Additionally, the final VO, at 282 Torr was reduced by 33.3% compared with 380 Torr (P < 0.01). At the termination of the exercise bout, the altitude specific maximal Voz was achieved (5). Arterial 0, saturation was monitored by ear oximetry throughout exercise (Table 1). Mean arterial 0, saturation at exhaustion was decreased with increasing altitude. The exercise satu ration data co1.lected by ear oximetry were consistent with saturation data obtai ned on arterial blood samples that were collected by invasive techniques on additional studies during Operation Everest II (5, 11, 20, 23, 24). RPE (Table 1) were collected for leg and breathing effort with use of the Borg scale (1). At exhaustion, the RPE for breathing were increased by 18 and 29% at 380 and 282 Torr, respectively, when compared with 760 Torr. The RPE for leg exercise were not significantly different regardless of altitude. At 760 Torr, the subjects scored a significantly higher rating for leg exercise when compared with breathing effort. RPE scores for leg and breathing effort were equivalent at 380 and 282 Torr. Plasma ammonium and blood lactate concentrations.

Plasma ammonium concentrations ([NH:]) before exercise at 760, 380, and 282 Torr were not significantly different at each altitude (Fig. I). At 760 Torr, postexercise [NH:] increased 1.6-fold when compared with preexercise and remained elevated after the 5- and 15-min recovery periods. However, after exhaustive exercise at 380 and 282 Torr, postexercise and recovery levels of [NH:] were not increased over preexercise values. Blood lactate concentrations ([Lac]) before exercise at 760,380, and 282 Torr were not significantly different at each altitude (Fig. 2). When compared with preexercise [ Lac], postexercise [ Lac] was increased 7-fold (11.0 t 1.2 mM) at 760 Torr, U-fold (8.1 t 0.8 mM) at 380 Torr, and 1.4-fold (5.2 t 0.7 mM) at 282 Torr. The increase in postexercise [Lac] at 760 Torr was greater than postexercise [Lac] at 380 (P < 0.05) or 282 Torr (P < 0.01). Also, postexercise [Lac] at 380 Torr was significantly greater than at 282 Torr (P c 0.05). After 5- and 15-min recovery at 760 and 380 Torr, [Lac] remained elevated compared

Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (137.154.019.149) on January 12, 2019.

2576

EXHAUSTIVE

1. Physiological parameters

TABLE

for incremental

EXERCISE

AT ALTITUDE

exercise to exhaustion Borg Scale-RPE

760 Torr 380 Torr 282 Torr

End vog, l/min

Power Output, w

4.1+0.2 2.4+O.lt 1.6r40.2Q

336.4k23.6 271.5+11.8t 177.0+_3*9.Q

Time to Exhaustion, min*

Sk,, %

Breath

Leg

11.8tl.l 9.5&0.6-t 6.1+0.2?$

95+1 63+3t 39+3t$

7.2kO.75 8.5+0.3”f 9.3*0.2t$

9.MO.3 8.Ot0*7 9.3k3.2

Values are means t SE. VO,, oxygen uptake; Sao,, arterial 0, saturation; RPE, rating of perceived exertion. * Exertion (does not include initial 3-min exercise without load). 7 P < 0.01 from 760 Torr; 3 P < 0.01 from 380 Torr; $ P < 0.05 from leg rating at 760 Torr. 300

r

a II H m

p7A

Pre - Exercise Post-Exercise 5- Min Recovery 15-Min Recovery

Pre- Exercise Post-Exercise 5-Min Recovery 15-Min Recovery

a,c,d T

I 760

282

BAROMETRIC

PRESSURE

BAROME

(TORR)

FIG. 1. Effect of altitude on plasma ammonium accumulation after incremental cycling exercise to exhaustion. Data are means + SE. a P < 0.05 from preexercise.

with preexercise values (P < 0.05). At 282 Torr, 5- and Smin recovery [Lac] were not elevated over preexercise [ Lac] . The change in plasma [NH:] and the change in blood [Lac] from preexercise to postexercise were correlated positively (r = 0.98, P < 0.01) at 760 Torr but were not correlated at 380 and 282 Torr. At 760 Torr, the change in [NH,+] from pre- to postexercise was 106 t 20 PM. This change is consistent with the findings of Buono et al. (3) for incremental cycling exercise to exhaustion. Plasma glucose, insulin, glucugun, and growth hormone concentrations. Resting plasma glucose concentrations at

760, 380, and 282 Torr were not significantly different (Table 2). At 760 Torr, postexercise plasma glucose concentrations were not increased compared with preexercise values but were increased by -34% after 5- and 15min recovery. At 380 Torr, plasma glucose concentrations increased 24 % postexercise and 58% after recovery compared with preexercise concentrations. At 380 Torr, plasma glucose concentrations after 5- and 15-min recovery were -1 .5% higher than corresponding values at 760 Torr. At 282 Torr, there were no differences between preand postexercise concentrations of plasma glucose, but concentrations were increased after 5- and 1.5-min recovery compared with preexercise. For plasma insulin at 760 Torr, there was no significant difference between pre- and postexercise insulin concentrations (Table 2). After 5- and 15-min recovery at 760 Torr, plasma insulin concentrations increased twofold. At 380 and 282 Torr, both pre- and postexercise plasma insulin concentrations were increased by approxi-

I

760

TRIG

380

PRESSURE

(TO

2. Effect of altitude on blood lactate accumulation after incremental cycling exercise to exhaustion. Data are means t SE. a P < 0.05 from preexercise; b P < 0.05 from 760 Torr; ’ P < 0.01 from 760 Torr; d P < 0.05 from 380 Torr. FIG.

mately twofold when compared with 760 Torr. Plasma insulin concentrations at 380 and 282 Torr remained elevated during the recovery period and were approximately twofold higher 15 min after exercise. At 380 and 282 Torr, plasma insulin concentrations after 15-min recovery were increased twofold over preexercise values. There were no significant altitude effects on plasma glucagon or the insulin-to-glucagon molar ratio. During the exercise bouts at each altitude, plasma glucagon concentrations remained constant, averaging -132 t 17 pM. Independent of altitude, the preexercise insulin-toglucagon molar ratio was 1.15 + 0.37 and did not change postexercise (1.15 t 0.39), but was increased to 1.65 t 0.41 and 1.80 t 0.48 after 5- and 15-min recovery, respectively (P < 0.02). Similarly, altitude per se induced no significant effects in plasma growth hormone concentrations. Preexercise concentrations averaged 4.69 t 1.6 rig/ml at each altitude. Plasma growth hormone concentrations increased significantly (P < 0.05) to 9.12 t 2.40 rig/ml postexercise and to 9.89 t- 1.89 and 10.95 t 2.46 rig/ml after 5- and 15-min recovery, respectively. Plasma catecholamine concentrations. Preexercise plasma norepinephrine concentrations ([NE]) were not significantly different with altitude exposure (Table 3). At 760 and 380 Torr, postexercise [NE] was increased -18- and 8-fold, respectively, when compared with preexercise values but returned to preexercise concentrations after 5- and 15-min recovery. When compared with preexercise at 282 Torr, plasma [NE] did not in-


EXHAUSTIVE

2577

EXERCISE AT ALTITUDE

TABLE 2. Effect of incremental exercise to exhaustion at extreme altitude on plasma glucose and insulin concentrations

4. Effect of incremental exercise to exhaustion at extreme altitude on plasma glycerol and FFA concentrations TABLE

Recovery

Recovery Preexercise

Postexercise

Preexercise

Postexercise

5 min

15 min

6.3~10.4” 7.6+0.4apb 6.4tO.2”

6.4-tO.3” 7.7+0.6asb 6.6+0.2”


165kl5

213+24

58+7-f 54+12”f

145?24”7 77tlOQ

981k23”” 116t32 141+29avd

82_+18” 150+26”~“~” 164k37apdpe

760 380 282

Torr Torr Torr

450t114 538t106 6962102

Values are means 2 SE. a P < 0.01 from preexercise; b P < 0.01 from and 282 Torr; ’ P < 0.05 from 760 Torr; d P < 0.01 from 760 Torr; e P < 0.05 from postexercise.

760

Torr 380 Torr 282 Torr

2.91~0.91

Plasma glucose, 760 Torr 380 Torr 282 Torr

4.7M.2 4.8M.3 5.1+0*1


41t30 87+1Bd 851k18~

mM

Plasma

5.3+0*1 6.0t0.4” 5.9H.I.3” Plasma insulin, pM 32k6 73219” 116k23ayd

760

crease significantly with exercise or during the recovery period. Similarly, preexercise plasma epinephrine concentrations ([EP]) were not significantly different with altitude exposure (Table 3). At 760 Torr, [EP] increased by -12, fold compared with preexercise values but returned to initial concentrations after 5- and 15-min recovery. At 380 Torr, postexercise [EP] was increased significantly over preexercise but was 60% lower than postexercise at 760 Torr. Plasma [EP] after 5- and 15-min recovery was not different from preexercise values at 380 Torr. At 282 Torr, there were no significant differences between plasma [EP] at preexercise, postexercise, or 5- and lomin recovery. At 282 Torr, postexercise [EP] was 86% lower than corresponding values at 760 Torr. Plasma glycerol, FFA, and triglyceride concentrations.

Preexercise plasma glycerol concentrations at 760 Torr were threefold higher than preexercise values at 380 and 282 Torr (Table 4). At 760 Torr, postexercise plasma glycerol concentrations did not increase significantly over preexercise values but increased by twofold after 5and 15-min recovery. At 380 Torr, plasma glycerol concentrations increased by 2.5-fold postexercise and by approximately 3-fold after 5- and 15-min recovery. At 282 Torr, plasma glycerol concentrations were not increased significantly with exercise or during recovery. Preexercise FFA concentrations were not significantly 3. Effect of incremental exercise to exhaustion at extreme altitude on plasma catecholamine concentrations

TABLE

Recovery Preexercise

Pmtexercise Plasma


1.24k0.21 2.55k0.25 3.73t1.18

Torr Torr Torr

0.27+0.09 0.17~0.04 0.15tO.02

nerepinephrine,

epinephrine,

3.37t1.40* 1.33+0.45*f 0.46+0.13t

15 min

nM

22.67%7.28* 21.03~16.27* 8.86+2.80t$ Plasma

760 380 282

5 min

5.21~1.50 11.14k1.34 5.92k1.30

2.20t0.53 6.30t1.48 4.49t0.59

0.80H.MI9 0.50~0.07 0.18tO.04

0.34tO.08 0.39t0.06 0.18t0.03

nM

Values are means + SE. * P < 0.05 from preexercise; t P < 0.05 from 760 Torr; $ P -=z0.05 from 380 Torr.

glycerol,

334t34* 191+22*.f 93+13t$

Glycerol

molar

1.94-tO.22*

3.88+1.09*$ 5.64+1.3O*t$

15 min

,uM

Plasma FFA peqll 419+91 695t92 564249 516tlO5 414+80 5652119 FFA:

9.00t1.36t 16.89+4.75t$

5 min

351+17* 181+35*-f82-+147$ 636t71 545t-54 599tl27

ratio

2.1 l-tO.25* 3.00+0.10*~

1.82t0.22* 3.44_+0.58*§

6.3Oi1.37*t$

7.49&1.38*?$

Values are means + SE. FFA, free fatty acid. * P < 0.01 from preexercise; 7 P < 0.01 from 760 Torr; 5 P < 0.01 from 380 Torr; 8 P < 0.05 from 760 Torr.

different at any of the altitudes and did not change with exercise or recovery (Table 4). At 760 Torr, the preexercise plasma FFA-to-glycerol molar ratio was ~3 and decreased significantly with exercise (Table 4). The preexercise FFA-to-glycerol molar ratio was elevated by 3.land 5.8-fold at 380 and 282 Torr, respectively, when compared with preexercise values at 760 Torr. At 380 Torr, the FFA-to-glycerol molar ratios at postexercise and 5- and 15min recovery were decreased by -55% when compared with the preexercise ratio. At 282 Torr, the FFA-to-glycerol molar ratios postexercise and 5- and 15-min recovery were decreased -67% when compared with preexercise. Preexercise plasma triglyceride concentration at 760 Torr was 0.69 t 0.13 mM. It increased to 1.11 t 0.28 mM at 380 Torr (P < O.Ol), and remained elevated at 282 Torr (1.25 t 0.22 mM). Plasma triglyceride concentrations did not change postexercise or during 5- and 15-min recovery at either altitude. DISCUSSION

This study examined the changes in circulating concentrations of substrates, metabolites, and key hormones that modulate substrate utilization during exercise. In light of the obligatory experimental design of Operation Everest II, interpretation of these data is complicated by simultaneously decreasing maximum exercise intensity, increasing hypoxemia, and increasing altitude exposure time. Therefore, our attempt to define the influence of altitude per se on factors that limit maximal exercise performance must be considered tentative. Endurance time, defined as time to exhaustion, for incremental cycling exercise decreased with increased simulated altitude exposure. This decrease in endurance capacity occurred despite sufficient concentrations of muscle ATP, glycogen, and phosphagens (10). Likewise, analysis of blood metabolites indicated that circulating concentrations of glucose and FFA were present in ample


2578

EXHAUSTIVE

EXERCISE

amounts. Despite the presence of these metabolic fuels, exercise endurance capacity was diminished. Endurance time has been hypothesized to vary as a function of glycogen stores and their rate of mobilization and breakdown by the glycolytic pathway, thus providing an anaerobic energy source (8). In the present study, analysis of muscle biopsy samples indicated there was no increase in the oxidative capacity, and resting muscle glycogen stores were not decreased with altitude exposure (9). Although ample amounts of energy substrates were present at extreme altitude, the muscle may not have been activated sufficiently to maintain adequate power output. Evidence for diminished activation was seen in the decreased concentrations of plasma epinephrine and norepinephrine after exercise at higher simulated altitude. Concurrently, plasma insulin concentrations were increased after exercise at 380 and 282 Torr. In exercising dogs, circulating insulin has been shown to inhibit hepatic glycogenolysis and lipolysis in opposition to ,& adrenergic activation (15). Conversely, insulin did not attenuate the glycogenolytic effects of epinephrine in rat muscle, but the synergistic actions of insulin and epinephrine on lipolysis were not examined (21, 28). It is possible that increased concentrations of insulin, combined with a decreased catecholamine response, may have contributed to the apparent lack of FFA mobilization during exercise. Because plasma FFA concentrations and the FFA turnover rate are positively correlated (16), decreased plasma accumulation of FFA could have resulted in decreased FFA utilization by exercising muscle. Decreased use of muscle glycogen with an apparent increase in oxidation of FFA has been reported during submaximal exercise in altitude acclimatized humans (29). Fat oxidation in muscle is important for exercise with work loads >70% Vo 2 fllaXover long periods (14). For short-term high-intensity exercise, however, oxidation of exogenously derived fuels, such as FFA, may not lead to enhanced endurance capacity. Fatigue has been defined as “disturbed homeostasis” (4). It is possible that one of the responses to high-intensity exercise at sea level, the accumulation of ammonium, may be essential for stimulation of glycolytic activity. An increase in blood levels of ammonium is associated with a concomitant increase in blood lactate (19). Our finding of reduced lactate and ammonium accumulations is consistent with the concept of reduced glycolytic activity. Because ammonium does not accumulate to the same degree with steady-state exercise (31) or during incremental exercise to exhaustion at altitude, the activity of the purine nucleotide cycle may be attenuated. Thus decreased purine nucleotide cycle activity at altitude may lead to reduced activation of glycolysis and limit mobilization and oxidation of intramuscular muscle stores of glycogen. This failure to stimulate the purine nucleotide cycle and, in turn, glycolytic activity may limit high-intensity exercise during extreme altitude exposure and increase the perturbation in exercise homeostasis. At altitude, this alteration of metabolism in response to high-intensity exercise may be important in lieu of the shift of muscle metabolism from anaerobic formation of

AT ALTITUDE

lactate to more complete oxidation of glycogen or FFA. Thus, with exhaustive exercise at extreme altitude exposure, fatigue may develop when the metabolic demand exceeds energy supply mechanisms with a concurrent impairment of activation or excitation. With regard to the psychological influences on endurance effort at altitude, it has been reported that central factors, rather than local, exert a greater effect on perceived effort when exercise levels are of sufficient magnitude to involve pulmonary sensations (12). In the present study, this phenomenon may have been operative because the subjects perceived breathing was more difficult at altitude than at sea level. This portion of Operation Everest II focused on identification of metabolic variables that may limit exhaustive exercise at extreme altitude. The limitation in exhaustive exercise performance may be related to a reduced capacity to use circulating substrates and mobilize energy stores. If so, the diminished circulating concentrations of lactate, ammonium, glycerol, and catecholamines may be the result of limited exercise capacity and not the cause. Participating scientists were James Alexander, Maureen Andrew, James Anhblm, Louis Banderet, Richard Burse, Jonathan Carter, Howard Green, Geoff Coates, Howard Donner, Ulrich Duncan, Genevieve Farese, Vincent Forte, Charles Fulco, Scott Garner, Bertron Groves, Harriet Gustaffson, Pet.er Hackett, Duncan MacDougall, Mark Malconian, Hugh O’Brodovich, Richard Meehan, Peter Powles, John T. Reeves, Robert Roach, Paul Rock, Madeleine Rose, Bruce Ruscio, Robert Schoene, Jose Suarez, Brenda Townes, Darlene Tyler, Laurie Trad, Peter Wagner, and Patricia Young. The authors appreciate the excellent support provided by the Altitude Chamber Crew, Jim Devine, Joe Gardella, and Ed Powers; and the constructive comments of Drs. Eldon W. Askew, Ralph P. Francesconi, Kent B. Pandolf, and Andrew J. Young. This study is one of a series titled “Operation Everest II,” describing a project that was sponsored by the Arctic Institute of North America and the US Army Research Institute of Environmental Medicine and funded by the US Army Medical Research and Development Command Contract DAMD 17-85-C-5206. The views, opinions, and/or findings contained herein 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. Principal investigators were Charles S. Houston, John R. Sutton, and Allen Cymerman. Address for reprint requests: P. M. Young, c/o Allen Cymerman, Altitude Physiology and Medicine, US Army Research Institute of Environmental Medicine, Natick, MA 01760-5007. Received 21 June 1991; accepted in final form 19 June 1992. REFERENCES 1. BORG, G. Perceived exertion as an indicator of somatic stress. J. Rehab. Med. 2: 92-98, 1970. 2. BRYLA, J., AND A. NIEDZWEICKA. Relationship between pyruvate carboxylation and citrulline synthesis in rat liver mitochondria: the effect of ammonia and energy. Int. J. Biochem. 10: 235-239,1979. 3. BUONO, M. J., T. R. CLANCY, AND J. R. COOK. Blood lactate and ammonium ion accumulation during graded exercise in humans. J. Appl. Hzysiol. 57: 135-139, 1984. 4. CHRISTENSEN, E. H. Muscular work and fatigue. In: Muscle as a Tissue, edited by K. Rodahl and S. M. Horvath. New York: McGraw-Hill, 1960, chapt. 9, p. 176-189. 5. 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. 6. EDWARDS, R. H. T. Biochemical basis of fatigue in exercise performance: catastrophe theory of muscle fatigue. In: Biochemistry of Exercise, edited by H. G. Knuttgen, J. A. Vogel, and J. Poortmans. Champaign, IL: Human Kinetics, 1983, vol. 13, p* 3-28. 7. FULCO, C. S., AND A. CYMERMAN. Human performance and acute


EXHAUSTIVE

EXERCISE

AT ALTITUDE

2579

hypoxia. In: Human Performance Physiology and Environmental Medicine at Terrestriat Extremes, edited by K. B. Pandolf, M. N. Sawka, and R. R. Gonzalez. Indianapolis, IN: Benchmark, 1988, p.

8.

9.

10.

11,

12.

13.

14.

15.

16. 17. 18.

19. 20.

21. SHIKAMA, H., J. CHIASSON, ANDJ. H. EXTON.Studies on the interactions between insulin and epinephrine in the control of skeletal muscle glycogen metabolism. J. Biol. Chem. 256: 4450-4454, 1981. 467-495. 22. SUGDEN, P. H., ANDE. A, NEWSHOLME. The effects of ammonium, GLESER, M. A., ANDJI A. VOGEL.Endurance exercise: effect of inorganic phosphate and potassium ions on the activity of phoswork-rest schedules and repeated testing. J. Appl. Physiol. 31: 735phofructokinase from muscle and nervous tissues of vertebrates 739,197l. and invertebrates. &o&em. J. 150: 113-122, 1975. GREEN, H. J., J. R.SUTTON,A. CYMERMAN, P. M. YOUNG,AND 23. SUTTON, J. R.J. T, REEVES,P. D. WAGNER, B. M. GROVES, A. C. S. HOVSTUN, Operation Everest II: adaptations in human skeleCYMERMAN, M.K. MALCONIAN, P. B. ROCK,P.M.YouNG,S. D. tal muscle. J. Appl. Physiol, 66: 2454-2461, 1989. WALTER,ANDC. S. HOUSTON. Operation Everest II: oxygen transport during exercise at extreme simulated altitude. J. Appl. Physiol. GREEN, H. J,, J. R. SUTTON,~. M, YOUNG, A. CYMERMAN, AND 64: 1309-1321,1988. C. S. HOUSTON. Operation Everest II: muscle energetics during 24. WAGNER, P. D., J. R. SUTTON, J. T. REEVES, A. CYMERMAN, B. M. maximal exhaustive exercise. J. Appl. Physiol. 66:142-150,1989. GROVES, ANDM. K. MALCONIAN. Operation Everest II: pulmonary GROVES, 3. M.,J. T. REEVES, J. R. SUTTON, P. D. WAGNER, A. gas exchange during a simulated ascent of Mt. Everest. J. Appk CYWIERMAN, M.K. MALCONIAN, P.B. ROCK, P.M. YOUNG,AND Physiol. 63: 2348-2359, 1987. C. S. HOUSTON. Operation Everest II: elevated high altitude pulmo25. WHEELER, T. J., ANDJ. M. LOWENSTEIN. Adenylate deaminase nary resistance unresponsive to oxygen. J. Appl. Physiol. 63: 521from rat muscle. J. Biol. Chem. 254: 8994-8999, 1979. 530,1987. 26. WILKERSON, J. E., D. L. BATTERTON, ANDS. M. HORVATH. AmmoHORSTMAN,D.H., R, WEISKOPF,AND S. ROBINSON. Thenatureof nia production following maximal exercise: treadmill vs. bicycle the perception of effort at sea level and high altitude. Med. Sci. testing. Eur. J. Appl. Physiol. Occup. Physiol. 34: 169-172, 1975. Sports 11: 150-154,1979. A., ANDM. ERECINSKA, Mechanism of inhibitory action HousToN,C.S.,J. R. SUTTON, A. CYMERMAN, ANDJ.T. REEVES. 27. WURCEL, of ammonia on the respiration of rat liver mitochondria. Biochim. Operation Everest II: man at extreme altitude. J. Appl. Physiol. 63: Biophys. Acta 65: 27-33, 1962. 877~882,1987. 28. YANG,H.T.,K.I. CARLSON,AND W.W. WINDER. Insulindoesnot HULTMAN,E., ANDH. SJOHOLM. Substrate availability. In: Biuinfluence muscle glycogenolysis in adrenomedullated exercising chemistry of Exercise, edited by H. G, Knuttgen, J. A. Vogel, and J. rats. Am. J. Physiol. 253 (Regulatory Integrative Camp. Physiol. 22): Poortmans. Champaign, IL: Human Kinetics, 1983, vol. 13, p. 63-

75. ISSEKUTZ, B. Role of beta-adrenergic

R535-R540,1987.

K. B. PANDOLF, J.J. receptors in mobilization of 29, YOUNG,A.J., W.J. EVANS,A. CYMERMAN, KNAPIK,ANDJ. T. MAHER.Sparing effect of chronic high-altitude energy sources in exercising dogs, J. Appl. Physiul. 44: 8694376, exposure on muscle glycogen utilization. J. Appl. PhysioZ. 52: 8571967. 862,1982. ISSEKUTZ, B., P. PAUL, H. L. MILLER,ANDM. BORTZ. Oxidation of 30. YOUNG,A. J., ANDP. M. YOUNG.Human acclimatization to high plasma FFA in lean and obese humans. Metabolism 17: 62-68,1968. terrestrial altitude. In: Human Performance Physiology and EnviLOWENSTEIN, J. M. Ammonia production in muscle and other tisronmental Medicine at Terrestrial Extremes, edited by K. B. Pansues: the purine nucleotide cycle. Physiol. Rev. 52: 382-414, 1972. dolf, M. N. Sawka, and R. R. Gonzalez. Indianapolis, IN: BenchMEYER,R. A., G.A. DUDLEY, ANDR. L, TEWUNG. Ammonia and mark, 1988,p.497-543. IMP in different skeletal muscle fibers after exercise in rats. J. 31. YOUNG, P. M.,P. B. RocK,C.S.FULCO, L, A. TRAD,V.A. FORTE, Appl. Physioot.49: 1037-1041, 1980. ANDA. CYMERMAN. Altitude acclimatization attenuates plasma MITCH, B. J. C., ANDE. W. BANNISTER. Ammonia metabolism in ammonia accumulation during submaximal exercise. J. Appl. Physexercise and fatigue. Med. Sci. Spurts Exercise 15: 41-50, 1983. iol. 63:758-764,1987. REEVES, J. T., B. M. GROVES, J. R. SUTTON, P. D. WAGNER, A. 32, YOUNG, P. M., M. S:ROSE, J. R. SUTTON, H. J. GREEN, A. CYMERCYMERMAN, M. K. MALCUNIAN,P.B.ROCK,P.M.YouNG, AND MAN,ANDC. S. HOUSTON. Operation Everest II: plasma lipid and C, S. HOUSTON, Operation Everest II: preservation of cardiac funchormonal responses during simulated ascent of Mt. Everest. J. tion at extreme altitude. J. Appl. Physiol. 63: 531-539, 1987. Appl. Physiol. 66: 1430-1435, 1989.


Metabolic, body temperature and hormonal responses to repeated periods of prolonged cycle-ergometer exercise in men.

Hormonal, metabolic, and cardiovascular responses to static exercise in humans: influence of epidural anesthesia.

Serum IGF-I and hormonal responses to incremental exercise in athletes with and without left ventricular hypertrophy.

Training-induced changes in hormonal and metabolic responses to submaximal exercise.

What limits performance during whole-body incremental exercise to exhaustion in humans?

Hormonal and growth factor responses to heavy resistance exercise protocols.

Stability and variability in hormonal responses to prolonged exercise.

Operation Everest II: structural adaptations in skeletal muscle in response to extreme simulated altitude.

The sleep electrocardiogram at extreme altitudes (Operation Everest II)

Acute exposure to cold air and metabolic responses to exercise.

Variations in serum magnesium and hormonal levels during incremental exercise.

Diminished hormonal responses to exercise in trained rats.

Hormonal responses to trauma.

Hormonal and metabolic responses to a resistance exercise protocol in lean children, obese children and lean adults.

Hormonal, metabolic, and cardiorespiratory responses of young and adult athletes to a single session of high-intensity cycle exercise.

Neuromuscular and metabolic responses to three different resistance exercise methods.

Prefrontal and motor cortex EEG responses and their relationship to ventilatory thresholds during exhaustive incremental exercise.

Physiological responses to incremental exercise in the heat following internal and external precooling.

Influence of dietary nitrate supplementation on physiological and cognitive responses to incremental cycle exercise.

Caffeine ingestion prior to incremental cycling to exhaustion in recreational cyclists.

Oxygen transport and cardiovascular function at extreme altitude: lessons from Operation Everest II.

Operation Everest II: arterial oxygen saturation and sleep at extreme simulated altitude.

Differences in the metabolic and hormonal response to exercise between racing cyclists and untrained individuals.

A Systematic Method to Detect the Metabolic Threshold from Gas Exchange during Incremental Exercise.