In this study we investigated the acute effects of high-altitude exposure and physical exercise on muscle protein synthesis. The fractional rate of muscle protein synthesis increased after active, but not passive ascent to high altitude, suggesting that exercise accounts for the observed effect. However, at high altitude, the volunteers also were subject to hypoxia and alkalosis, which also have the potential to influence protein synthesis.
High-altitude exposure may lead to considerable weight loss, possibly related to direct effects of hypoxia (14). Accordingly, acute hypobaric hypoxia has been shown to decrease the turnover of leucine and its uptake from the forearm muscle compartment, a measure of protein synthesis (33). Moreover, normobaric hypoxia, as observed in chronic obstructive pulmonary disease, is often accompanied by marked muscle atrophy (22). Also, prolonged severe hypoxia has been shown to result in a reduced body and muscle mass and decreased activities of enzymes of the oxidative pathways in skeletal muscle tissue (12). In rats, moderate hypoxia (10% O2) for 6 h was shown to inhibit protein synthesis in the liver and heart (27,28), but severe hypoxia (5% O2) or 24 h of less severe hypoxia (10% O2) was required to inhibit protein synthesis in skeletal muscle. Thus, in the present study, exposure to an altitude of 4559 m, with a pO2 similar to that of 10% O2 at sea level, was possibly not severe enough to induce a negative protein balance.
Hypoxia at high altitude is also accompanied by alkalosis. A number of studies have indicated that pH is a regulator of protein synthesis. Metabolic acidosis induced with ammonium chloride was shown to inhibit muscle protein synthesis in rats (4) and humans (16). Moreover, respiratory acidosis induced by breathing 12% CO2 (3) also lowered muscle protein synthesis in rats. Accordingly, in hyperventilated patients with head trauma who are alkalotic, the rate of muscle protein synthesis fell when hyperventilation was discontinued, resulting in a fall in arterial pH (40). In the present study, the mean oxygen tension and the degree of respiratory alkalosis were not different between the two groups. It is therefore possible that respiratory alkalosis compensates for any possible negative effects of hypoxia in the air group. However, the increase of FSR in the foot group is related to exercise alone, as pH and pO2 were the same in the two groups.
The concentrations of various hormones involved in the regulation of protein synthesis have been shown to change after exposure to acute and chronic hypoxia, and increased growth hormone and thyroid hormone concentrations have been described previously (41). However, the present study showed no influence of high-altitude exposure, with or without exercise, on plasma IGF-1, TSH, fT4, or T3 concentrations. Glucocorticoids also are important in mediating changes in protein metabolism. In muscle it is known that glucocorticoids can suppress protein synthesis (29,30). This catabolic action has been demonstrated in animal tissues in vitro (19,32) and in vivo (9,38). The significantly higher increase of 24-h cortisol excretion in the foot group relative to the air group suggests that the increase in protein synthesis rates might be the net result of stimulation by exercise despite attenuation by glucocorticoids. Similarly, there was no indication of an increase in the concentrations of branched chain amino acids and glutamine, which have been reported to enhance muscle protein synthesis (10).
There are very few data regarding the effect of exercise on skeletal muscle protein metabolism at high altitude. It has been hypothesized that loss of muscle mass at high altitude in elite climbers may be due to a relative lack of exercise, which may lead to muscle atrophy, loss of appetite, and maldigestion or malabsorption (15,36). Disuse can contribute to muscle loss, and passive stretching can preserve the architecture of muscle fibers in critically ill patients (11). Moreover, in animal models, exercise has a dramatic effect on the rate of muscle protein synthesis depending on several factors, such as intensity, duration, and mode of exercise (35). The rate of muscle protein synthesis has been shown to be increased after resistance exercise in both human beings and rats, whereas synthesis rates were decreased after endurance exercise in most animal studies (35). In human beings, Tipton el al. could find no significant change in deltoid muscle protein synthesis after an intense 1.5-h swimming workout (39). In contrast, Carraro et al. have shown that muscle protein synthesis measured in volunteers at rest, at the end of 4 h of aerobic exercise, and again after 4 h of recovery was not different in the vastus lateralis muscle at the end of exercise compared with rest, but increased significantly by 25% during the recovery period (2). The discrepancy between the two studies could be attributed to the fact that the swimmers in Tipton's study were highly trained, were adapted, and might therefore not increase muscle protein synthesis rates further. MacDougall et al. found that 24 h after heavy resistance exercise, muscle protein synthesis in humans more than doubled (18), and it was shown that the elevation of muscle protein synthesis was maintained for 48 h after the exercise bout (24). However, the time course of the response to dynamic exercise in humans is less clear. The subjects in Carraro's study (2) walked on a treadmill for 4 h at 40% of maximal oxygen uptake, which is comparable with the aerobic exercise of long-duration climbing for 4-5 h in the present study. Furthermore, Sheffield-Moore et al. have shown that a single bout of moderate-intensity aerobic exercise is sufficient to increase the postexercise synthesis rates of muscle at low altitude (37). Aerobic exercise consisted of a 45-min walk on a treadmill at 40% of maximal oxygen uptake. Muscle protein synthesis increased significantly for up to 1 h by 45% in young and by 112% in elderly men, but returned to baseline by 3 h of recovery (37). In line with these findings, the present results clearly show an increase in muscle FSR. This increase is maintained for up to 1 d. The 35% increase in muscle FSR in the present study, which is markedly lower than the 112% in the elderly men in Sheffield's study, could be due to the fact that we measured muscle FSR only after 19-23 h after a long-duration exercise, or that a stimulation of muscle FSR might have been blunted by hypoxia, even after a short exposure to high altitude.
Finally, as a consequence of exercise, measurements of the rate of muscle protein breakdown, based on the excretion of 3-methylhistidine, have shown inconsistent results. Some studies reported increased (2,6,42), no change in (25,26), or decreased (23,31) excretion of 3-methylhistidine. Carraro found no effect of exercise on 3-methylhistidine excretion when the subjects received 1 g·kg−1·d−1 of protein, but there was a significant increase when protein intake was 2.5 g·kg−1·d−1 (2). The foot group in the present study had a protein intake of 1.1 g·kg−1·d−1 (LA), 1.1 g·kg−1·d−1 (HA1), 1.2 g·kg−1·d−1 (HA2), and 0.8 g·kg−1·d−1 (HA3). Thus, in line with the results of Carraro, we found no effect of exercise on urinary 3-methylhistidine excretion. Therefore, the results of 3-methylhistidine excretion are difficult to interpret, and it should be noted that 3-methylhistidine excretion may not entirely reflect skeletal muscle protein breakdown (2,34).
In conclusion, in the present study, in the subjects at 4559-m elevation there was no detectable change in muscle protein degradation, and an increase in muscle protein synthesis in those who actively climbed, despite significant hypoxia.
This study was supported by the Swiss National Science Foundation, grant Nr. 32-037560.93 (to P.E.B.). There were no conflicts of interest. We would like to thank the volunteers for their cooperation; Mr. Max Ballmer (deceased) of the Swiss Alpine Clup (Sektion Basel) for help in the recruitment of the volunteers; the Sezione Varallo del Clup Alpino Italiano and the nurses of the Department of Internal Medicine, University of Berne for providing the facilities at the Capanna Regina Margherita and at the hospital; and the Swiss army for providing and transport of the mobile x-ray unit.
Part of this study was presented at the "Hypoxia" Symposium at Lake Louise, 1995; the Congress of the American Society for Parenteral and Enteral Nutrition, Washington 1996, and was published in abstract form: Imoberdorf, R., P. J. Garlick, M. A. McNurlan, P. Bärtsch, M. Turgay, and P. E. Ballmer. Increase in muscle protein synthesis after active but not passive ascent to high altitude. Eur. J. Clin. Invest. 26(Suppl 1):58, 1996. Abstract.
1. Ballmer, P. E., M. A. McNurlan, E. Milne, et al. Measurement of albumin synthesis in man: A new approach, employing stable isotopes. Am. J. Physiol.
2. Carraro, F., Ch.A. Stuart, W. H. Hartl, J. Rosenblatt, and R. R. Wolfe. Effect of exercise and recovery on muscle protein synthesis in human subjects. Am. J. Physiol.
3. Calder, A. G., S. E. Anderson, I. Grant, M. A. McNurlan, and P. J. Garlick. The determination of low d5-phenylalanine enrichment (0.002-0.09 atom percent excess) after conversion to phenylethylamine, in relation to protein turnover studies by gas chromatography/electron ionization mass spectrometry. Rapid Commun. Mass Spectrom.
4. Caso, G., B. Tyndall, D. Sasvary, G. Casella, and P. J. Garlick. Muscle protein synthesis is depressed by acute respiratory acidosis. FASEB J.
5. Caso, G., B. A. Garlick, G. A. Casella, D. Sasvary, and P. J. Garlick. Acute metabolic acidosis inhibits muscle protein synthesis in rats. Am. J. Physiol.
6. Dohm, G. L., G. J. Kasperek, E. B. Tapscott, and G. R. Beecher. Effect of exercise on synthesis and degradation of muscle protein. Biochem. J.
7. Ferretti, G., H. Hauser, and P. E. di Prampero. Maximal muscular power before and after exposure to chronic hypoxia. Int. J. Sports Med.
11(Suppl 1):S31-S34, 1990.
8. Fuller, S. J., C. J. Gaitanaki, and S. H. Sudgen. Effects of increasing extracellular pH on protein synthesis and protein degradation in the perfused working rat heart. Biochem. J.
9. Garlick, P. J., I. Grant, and R. T. Glennie. Short-term effects of corticosterone treatment on muscle protein synthesis in relation to feeding. Biochem. J.
10. Garlick, P. J. The role of leucine in the regulation of protein metabolism. J. Nutr.
11. Griffiths, R. D., T. E. A. Palmer, T. Helliwell, P. MacLennan, and R. R. MacMillan. Effect of passive stretching on the wasting of muscle in the critically ill. Nutrition
12. Hoppeler, H., and D. Desplanches. Muscle structural modifications in hypoxia. Int. J. Sports Med.
13(Suppl 1):S166-S168, 1992.
13. Imoberdorf, R., P. J. Garlick, M. A. McNurlan, et al. Enhanced synthesis of albumin and fibrinogen at high altitude. J. Appl. Physiol.
14. Kayser, B. Nutrition and high altitude exposure. Int. J. Sports Med.
13(Suppl 1):S129-132, 1992.
15. Kayser, B., K. Acheson, J. Decombaz, E. Fern, and P. Cerretelli. Protein absorption and energy digestibility at high altitude. J. Appl. Physiol.
16. Kleger, J. R., M. Turgay, R. Imoberdorf, M. A. Mcnurlan, P. J. Garlick, and P. E. Ballmer. Acute metabolic acidosis decreases muscle protein synthesis but not albumin synthesis in humans. Am. J. Kidney Dis.
17. Lauber, K. Photometric determination of nitrogen. Wet incineration followed by formation of indophenol blue with salicylate/hypochlorite. Clin. Chim. Acta
18. MacDougall, J. D., M. J. Gibala, M. A. Tarnopolsky, J. R. MacDonald, S. A. Interisano, and K. E. Yarasheski. The time course for elevated muscle protein synthesis following heavy resistance exercise. Can. J. Appl. Physiol.
19. McGrath, J. A., and D. F. Goldspink. Glucocorticoid action on protein synthesis and protein breakdown in isolated skeletal muscles. Biochem. J.
20. McNurlan, M. A., P. Essen, S. D. Heys, V. Buchnan, P. J. Garlick, and J. Wernermann. Measurement of protein synthesis in human skeletal muscle: Further investigation of the flooding technique. Clin. Sci.
21. McNurlan, M. A., P. Essen, A. Thorell, et al. Response of protein synthesis in human skeletal muscle to insulin: An investigation with [2
ring]phenylalanine. Am. J. Physiol.
22. Morrison, W. L., J. N. A. Gibson, C. Scrimgeour, and M. J. Rennie. Muscle wasting in emphysema. Clin. Sci.
23. Mussini, E., L. Colombo, G. DePonte, M. Calzi, and F. Marcucci. Effect of swimming on protein degradation: 3-mehtylhistidine and creatinine excretion. Biochem. Med.
24. Phillips, S. M., K. D. Tipton, A. Aarsland, and S. E. Wolf, and R. R. Wolfe. Mixed muscle protein synthesis and breakdown after resistance exercise in humans. Am. J. Physiol.
25. Plante, P. D., and M. E. Houston. Effects of concentric and eccentric exercise on protein catabolism in man. Int. J. Sports Med.
26. Plante, R. I., and M. E. Houston. Exercise and protein catabolism in women. Ann. Nutr. Metab.
27. Preedy, V. R., D. M. Smith, and P. H. Sugden. The effects of 6 hours of hypoxia on protein synthesis in rat tissues in vivo
and in vitro
. Biochem. J.
28. Preedy, V. R., and P. H. Sugden. The effects of fasting or hypoxia on rates of protein synthesis in vivo in subcellular fractions of rat heart and gastrocnemius muscle. Biochem. J.
29. Radha, E., and S. P. Bessman. Effect of exercise on protein degradation: 3-methylhistidine and creatinine excretion. Biochem. Med.
30. Rannels, S. R., D. E. Rannels, A. L. Pegg, and L. S. Jefferson. Glucocorticoid effects on peptide-chain initiation in skeletal muscle and heart. Am. J. Physiol.
31. Rannels, S. R., and L. S. Jefferson. Effects of glucocorticoids on muscle protein turnover in perfused rat hemicorpus. Am. J. Physiol.
32. Reeds, P. J., and R. M. Palmer. Changes in prostaglandin release associated with inhibition of muscle protein synthesis by dexamethasone. Biochem. J.
33. Rennie, M. J., P. Babij, J. R. Sutton, et al. Effects of acute hypoxia on forearm leucine metabolism. Prog. Clin. Biol. Res.
34. Rennie, M. J., and D. J. Millward. 3-methylhistidine excretion and the urinary 3-methylhistidine/creatinine ratio are poor indicators of skeletal muscle protein breakdown. Clin. Sci.
35. Rennie, M. J., and K. D. Tipton. Protein and amino acid metabolism during and after exercise and the effects of nutrition. Annu. Rev. Nutr.
36. Rose, M. S., C. S. Houston, C. S. Fulco, G. Coates, J. R. Sutton, and A. Cyberman. Operation Everest II: Nutrition and body composition. J. Appl. Physiol.
37. Sheffield-Moore, M., C. W. Yeckel, E. Volpi, et al. Postexercise protein metabolism in older and younger men following moderate-intensity aerobic exercise. Am. J. Physiol. Endocrinol. Metab.
38. Southorn, B. G., R. M. Palmer, and P. J. Garlick. Acute effects of corticosterone on tissue protein synthesis and insulin-sensitivity in rats in vivo
. Biochem. J.
39. Tipton, K. D., A. A. Ferrando, B. D. Williams, and R. R. Wolfe. Muscle protein metabolism in female swimmers after a combination of resistance and endurance exercise. J. Appl. Physiol.
40. Vosswinkel, J. A., C. E. Brathwaite, T. R. Smith, J. M. Ferber, G. Casella, and P. J. Garlick. Hyperventilation
increases muscle protein synthesis in critically ill trauma patients. J. Surg. Res.
41. Ward, M. P., J. S. Milledge, and J. B. West. High Altitude Medicine and Physiology
, 3rd ed. London: Arnold, Hodder Headline Group, 2000, pp. 186-189.
42. Wolfe, R. R. Protein supplements and exercise. Am. J. Clin. Nutr.