High Altitude pp 191-202 | Cite as

Skeletal Muscle Tissue Changes with Hypoxia

  • Hans Hoppeler
  • Matthias Mueller
  • Michael Vogt


This review summarizes results of research into the effect on skeletal muscle tissue of prolonged exposure to high (3,000–5,500 m) and extreme altitude (>5,500 m). There is consensual evidence that continued sojourn at these altitudes has a number of negative consequences to muscle tissue. There is a loss of muscle mass related to a decrease of individual muscle fiber cross-sectional area. There is also a relative and absolute decrease in muscle oxidative capacity which manifests itself as a decrease in mitochondrial volume as well as a decrease in oxidative enzyme activities. The capillary to fiber ratio is maintained in hypoxia with the consequence that, without capillary neoformation, the oxygen supply of remaining mitochondria is improved. There is further a massive increase in lipofuscin, a lipid peroxidation product. Hypoxia activates defensive cellular mechanisms, among them the well-characterized response to the hypoxic master gene HIF (hypoxia-inducible factor). Reactive oxygen species (ROS) abound under hypoxic conditions and are further responsible for the orchestration of the hypoxia response. The permanent hypoxic stress of living at high altitude has led to a number of disparate but effective phylogenetic adaptations in native high-altitude populations, Tibetans and Quechua. When hypoxia is used as an adjunct limited to exercise training sessions, skeletal muscle tissue responds with a specific molecular signature. The functional consequences of which may offer benefits for competition at altitude.


Skeletal Muscle Tissue Oxidative Enzyme Activity Muscle Oxidative Capacity Fiber Type Distribution Chronic Mountain Sickness 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Pugh LG, Gill MB, Lahiri S, et al. Muscular exercise at great altitudes. J Appl Physiol. 1964;19:431–40.PubMedGoogle Scholar
  2. 2.
    Valdivia E. Total capillary bed in striated muscles of guinea pigs native to the Peruvian mountains. Am J Physiol. 1958;194:585–9.PubMedGoogle Scholar
  3. 3.
    Reynafarje B. Myoglobin content and enzymatic activity of muscle and altitude adaptation. J Appl Physiol. 1962;17:301–5.PubMedGoogle Scholar
  4. 4.
    Hochachka PW, Stanley C, Merkt J, et al. Metabolic meaning of elevated levels of oxidative enzymes in high altitude adapted animals: an interpretive hypothesis. Respir Physiol. 1983;52:303–13.PubMedCrossRefGoogle Scholar
  5. 5.
    Banchero N. Cardiovascular responses to chronic hypoxia. Annu Rev Physiol. 1987;49:465–76.PubMedCrossRefGoogle Scholar
  6. 6.
    Holloszy JO, Booth FW. Biochemical adaptations to endurance exercise in muscle. Annu Rev Physiol. 1976;38:273–91.PubMedCrossRefGoogle Scholar
  7. 7.
    Himms-Hagen J, Cerf J, Desautels M, et al. Thermogenic mechanisms and their control. Experientia Suppl. 1978;32:119–34.PubMedCrossRefGoogle Scholar
  8. 8.
    Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 1992;12:5447–54.PubMedGoogle Scholar
  9. 9.
    Semenza GL, Shimoda LA, Prabhakar NR. Regulation of gene expression by HIF-1. Novartis Found Symp. 2006;272:2–8. discussion 8−14, 33–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Semenza GL. Oxygen homeostasis. Wiley Interdiscip Rev Syst Biol Med. 2010;2:336–61.PubMedCrossRefGoogle Scholar
  11. 11.
    Cerretelli P. Limiting factors to oxygen transport on Mount Everest. J Appl Physiol. 1976;40:658–67.PubMedGoogle Scholar
  12. 12.
    Ferretti G. Limiting factors to oxygen transport on Mount Everest 30 years after: a critique of Paolo Cerretelli’s contribution to the study of altitude physiology. Eur J Appl Physiol. 2003;90:344–50.PubMedCrossRefGoogle Scholar
  13. 13.
    Hoppeler H, Luthi P, Claassen H, et al. The ultrastructure of the normal human skeletal muscle. A morphometric analysis on untrained men, women and well-trained orienteers. Pflugers Arch. 1973;344:217–32.PubMedCrossRefGoogle Scholar
  14. 14.
    Cerretelli P, Hoppeler H. Morphologic and metabolic response to chronic hypoxia: the muscle system. In: Fregly MJ, Blatteis CM, editors. Handbook of physiology, section 4, environmental physiology, vol. 2. New York: Oxford University Press; 1996. p. 1155–81.Google Scholar
  15. 15.
    Bartsch P, Saltin B. General introduction to altitude adaptation and mountain sickness. Scand J Med Sci Sports. 2008;18 Suppl 1:1–10.PubMedCrossRefGoogle Scholar
  16. 16.
    Hoppeler H, Howald H, Cerretelli P. Human muscle structure after exposure to extreme altitude. Experientia. 1990;46:1185–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Butterfield GE, Gates J, Fleming S, et al. Increased energy intake minimizes weight loss in men at high altitude. J Appl Physiol. 1992;72:1741–8.PubMedGoogle Scholar
  18. 18.
    Kayser B, Narici M, Milesi S, et al. Body composition and maximum alactic anaerobic performance during a one month stay at high altitude. Int J Sports Med. 1993;14:244–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Kayser B, Acheson K, Decombaz J, et al. Protein absorption and energy digestibility at high altitude. J Appl Physiol. 1992;73:2425–31.PubMedGoogle Scholar
  20. 20.
    Westerterp KR, Meijer EP, Rubbens M, et al. Operation Everest III: energy and water balance. Pflugers Arch. 2000;439:483–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Tschop M, Morrison KM. Weight loss at high altitude. Adv Exp Med Biol. 2001;502:237–47.PubMedCrossRefGoogle Scholar
  22. 22.
    Raguso CA, Guinot SL, Janssens JP, et al. Chronic hypoxia: common traits between chronic obstructive pulmonary disease and altitude. Curr Opin Clin Nutr Metab Care. 2004;7:411–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Grosfeld A, Zilberfarb V, Turban S, et al. Hypoxia increases leptin expression in human PAZ6 adipose cells. Diabetologia. 2002;45:527–30.PubMedCrossRefGoogle Scholar
  24. 24.
    Tschop M, Strasburger CJ, Hartmann G, et al. Raised leptin concentrations at high altitude associated with loss of appetite. Lancet. 1998;352:1119–20.PubMedCrossRefGoogle Scholar
  25. 25.
    Benso A, Broglio F, Aimaretti G, et al. Endocrine and metabolic responses to extreme altitude and physical exercise in climbers. Eur J Endocrinol. 2007;157: 733–40.PubMedCrossRefGoogle Scholar
  26. 26.
    Hoppeler H, Kleinert E, Schlegel C, et al. Morphological adaptations of human skeletal muscle to chronic hypoxia. Int J Sports Med. 1990;11 Suppl 1:S3–9.PubMedCrossRefGoogle Scholar
  27. 27.
    MacDougall JD, Green HJ, Sutton JR, et al. Operation Everest II: structural adaptations in skeletal muscle in response to extreme simulated altitude. Acta Physiol Scand. 1991;142:421–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Mizuno M, Savard GK, Areskog NH, et al. Skeletal muscle adaptations to prolonged exposure to extreme altitude: a role of physical activity? High Alt Med Biol. 2008;9:311–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Vigano A, Ripamonti M, De Palma S, et al. Proteins modulation in human skeletal muscle in the early phase of adaptation to hypobaric hypoxia. Proteomics. 2008;8:4668–79.PubMedCrossRefGoogle Scholar
  30. 30.
    Baar K, Nader G, Bodine S. Resistance exercise, muscle loading/unloading and the control of muscle mass. Essays Biochem. 2006;42:61–74.PubMedCrossRefGoogle Scholar
  31. 31.
    Holm L, Haslund ML, Robach P, et al. Skeletal muscle myofibrillar and sarcoplasmic protein synthesis rates are affected differently by altitude-induced hypoxia in native lowlanders. PLoS One. 2010;5:e15606.PubMedCrossRefGoogle Scholar
  32. 32.
    Murray AJ. Metabolic adaptation of skeletal muscle to high altitude hypoxia: how new technologies could resolve the controversies. Genome Med. 2009;1:117.PubMedCrossRefGoogle Scholar
  33. 33.
    Green HJ, Sutton JR, Cymerman A, et al. Operation Everest II: adaptations in human skeletal muscle. J Appl Physiol. 1989;66:2454–61.PubMedGoogle Scholar
  34. 34.
    Takahashi H, Kikuchi K, Nakayama H. Effect of chronic hypoxia on skeletal muscle fiber type in adult male rats. Ann Physiol Anthropol. 1992;11:625–30.PubMedCrossRefGoogle Scholar
  35. 35.
    Doria C, Toniolo L, Verratti V, et al. Improved VO2 uptake kinetics and shift in muscle fiber type in high-altitude trekkers. J Appl Physiol. 2011;111:1597–605.PubMedCrossRefGoogle Scholar
  36. 36.
    Whittom F, Jobin J, Simard PM, et al. Histochemical and morphological characteristics of the vastus lateralis muscle in patients with chronic obstructive pulmonary disease. Med Sci Sports Exerc. 1998;30:1467–74.PubMedCrossRefGoogle Scholar
  37. 37.
    Pereira MC, Isayama RN, Seabra JC, et al. Distribution and morphometry of skeletal muscle fibers in patients with chronic obstructive pulmonary disease and chronic hypoxemia. Muscle Nerve. 2004;30:796–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Gosker HR, Zeegers MP, Wouters EF, et al. Muscle fibre type shifting in the vastus lateralis of patients with COPD is associated with disease severity: a systematic review and meta-analysis. Thorax. 2007;62: 944–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Saltin B, Nygaard E, Rasmussen B. Skeletal muscle adaptation in man following prolonged exposure to high altitude (abstract). Acta Physiol Scand. 1998; 109:31A.Google Scholar
  40. 40.
    Breen E, Tang K, Olfert M, et al. Skeletal muscle capillarity during hypoxia: VEGF and its activation. High Alt Med Biol. 2008;9:158–66.PubMedCrossRefGoogle Scholar
  41. 41.
    Olfert IM, Breen EC, Mathieu-Costello O, et al. Skeletal muscle capillarity and angiogenic mRNA levels after exercise training in normoxia and chronic hypoxia. J Appl Physiol. 2001;91:1176–84.PubMedGoogle Scholar
  42. 42.
    Lundby C, Pilegaard H, Andersen JL, et al. Acclimatization to 4100 m does not change capillary density or mRNA expression of potential angiogenesis regulatory factors in human skeletal muscle. J Exp Biol. 2004;207:3865–71.PubMedCrossRefGoogle Scholar
  43. 43.
    Mathieu-Costello O. Muscle adaptation to altitude: tissue capillarity and capacity for aerobic metabolism. High Alt Med Biol. 2001;2:413–25.PubMedCrossRefGoogle Scholar
  44. 44.
    Schoch HJ, Fischer S, Marti HH. Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain. Brain. 2002;125:2549–57.PubMedCrossRefGoogle Scholar
  45. 45.
    Howald H, Pette D, Simoneau JA, et al. Effect of chronic hypoxia on muscle enzyme activities. Int J Sports Med. 1990;11 Suppl 1:S10–4.PubMedCrossRefGoogle Scholar
  46. 46.
    Vogt M, Puntschart A, Geiser J, et al. Molecular adaptations in human skeletal muscle to endurance training under simulated hypoxic conditions. J Appl Physiol. 2001;91:173–82.PubMedGoogle Scholar
  47. 47.
    Zoll J, Ponsot E, Dufour S, et al. Exercise training in normobaric hypoxia in endurance runners. III. Muscular adjustments of selected gene transcripts. J Appl Physiol. 2006;100:1258–66.PubMedCrossRefGoogle Scholar
  48. 48.
    Chavez A, Miranda LF, Pichiule P, et al. Mitochondria and hypoxia-induced gene expression mediated by hypoxia-inducible factors. Ann N Y Acad Sci. 2008; 1147:312–20.PubMedCrossRefGoogle Scholar
  49. 49.
    Taylor CT. Mitochondria and cellular oxygen sensing in the HIF pathway. Biochem J. 2008;409:19–26.PubMedCrossRefGoogle Scholar
  50. 50.
    Semenza GL. Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology (Bethesda). 2009;24:97–106.CrossRefGoogle Scholar
  51. 51.
    Zhang JZ, Behrooz A, Ismail-Beigi F. Regulation of glucose transport by hypoxia. Am J Kidney Dis. 1999;34:189–202.PubMedCrossRefGoogle Scholar
  52. 52.
    Webster KA. Evolution of the coordinate regulation of glycolytic enzyme genes by hypoxia. J Exp Biol. 2003;206:2911–22.PubMedCrossRefGoogle Scholar
  53. 53.
    Katz A. Modulation of glucose transport in skeletal muscle by reactive oxygen species. J Appl Physiol. 2007;102:1671–6.PubMedCrossRefGoogle Scholar
  54. 54.
    Martinelli M, Winterhalder R, Cerretelli P, et al. Muscle lipofuscin content and satellite cell volume is increased after high altitude exposure in humans. Experientia. 1990;46:672–6.PubMedCrossRefGoogle Scholar
  55. 55.
    Askew EW. Work at high altitude and oxidative stress: antioxidant nutrients. Toxicology. 2002;180:107–19.PubMedCrossRefGoogle Scholar
  56. 56.
    Terman A, Brunk UT. Lipofuscin. Int J Biochem Cell Biol. 2004;36:1400–4.PubMedCrossRefGoogle Scholar
  57. 57.
    Rajawat YS, Hilioti Z, Bossis I. Aging: central role for autophagy and the lysosomal degradative system. Ageing Res Rev. 2009;8:199–213.PubMedCrossRefGoogle Scholar
  58. 58.
    Allaire J, Maltais F, LeBlanc P, et al. Lipofuscin accumulation in the vastus lateralis muscle in patients with chronic obstructive pulmonary disease. Muscle Nerve. 2002;25:383–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Koechlin C, Maltais F, Saey D, et al. Hypoxaemia enhances peripheral muscle oxidative stress in chronic obstructive pulmonary disease. Thorax. 2005;60: 834–41.PubMedCrossRefGoogle Scholar
  60. 60.
    Hurtado A, Rotta A, Merino C, et al. Studies of my hemoglobin at high altitudes. Am J Med Sci. 1937; 194:708–13.CrossRefGoogle Scholar
  61. 61.
    Conley KE, Ordway GA, Richardson RS. Deciphering the mysteries of myoglobin in striated muscle. Acta Physiol Scand. 2000;168:623–34.PubMedCrossRefGoogle Scholar
  62. 62.
    Garry DJ, Kanatous SB, Mammen PP. Emerging roles for myoglobin in the heart. Trends Cardiovasc Med. 2003;13:111–6.PubMedCrossRefGoogle Scholar
  63. 63.
    Wystub S, Ebner B, Fuchs C, et al. Interspecies comparison of neuroglobin, cytoglobin and myoglobin: sequence evolution and candidate regulatory elements. Cytogenet Genome Res. 2004;105:65–78.PubMedCrossRefGoogle Scholar
  64. 64.
    Kanatous SB, Mammen PP, Rosenberg PB, et al. Hypoxia reprograms calcium signaling and regulates myoglobin expression. Am J Physiol Cell Physiol. 2009;296:C393–402.PubMedCrossRefGoogle Scholar
  65. 65.
    Masuda K, Okazaki K, Kuno S, et al. Endurance training under 2500-m hypoxia does not increase myoglobin content in human skeletal muscle. Eur J Appl Physiol. 2001;85:486–90.PubMedCrossRefGoogle Scholar
  66. 66.
    Pattengale PK, Holloszy JO. Augmentation of skeletal muscle myoglobin by a program of treadmill running. Am J Physiol. 1967;213:783–5.PubMedGoogle Scholar
  67. 67.
    Juel C, Lundby C, Sander M, et al. Human skeletal muscle and erythrocyte proteins involved in acid–base homeostasis: adaptations to chronic hypoxia. J Physiol. 2003;548:639–48.PubMedCrossRefGoogle Scholar
  68. 68.
    Desplanches D, Hoppeler H, Tuscher L, et al. Muscle tissue adaptations of high-altitude natives to training in chronic hypoxia or acute normoxia. J Appl Physiol. 1996;81:1946–51.PubMedGoogle Scholar
  69. 69.
    Hoppeler H, Howald H, Conley K, et al. Endurance training in humans: aerobic capacity and structure of skeletal muscle. J Appl Physiol. 1985;59:320–7.PubMedGoogle Scholar
  70. 70.
    Rosler K, Hoppeler H, Conley KE, et al. Transfer effects in endurance exercise. Adaptations in trained and untrained muscles. Eur J Appl Physiol Occup Physiol. 1985;54:355–62.PubMedCrossRefGoogle Scholar
  71. 71.
    Elder GC, Bradbury K, Roberts R. Variability of fiber type distributions within human muscles. J Appl Physiol. 1982;53:1473–80.PubMedGoogle Scholar
  72. 72.
    Favier R, Spielvogel H, Desplanches D, et al. Maximal exercise performance in chronic hypoxia and acute normoxia in high-altitude natives. J Appl Physiol. 1995;78:1868–74.PubMedGoogle Scholar
  73. 73.
    Hochachka PW, Gunga HC, Kirsch K. Our ancestral physiological phenotype: an adaptation for hypoxia tolerance and for endurance performance? Proc Natl Acad Sci U S A. 1998;95:1915–20.PubMedCrossRefGoogle Scholar
  74. 74.
    Aldenderfer MS. Moving up the world: archeologists seek to understand how and when people came to occupy the Andean and Tibetan plateaus. Am Sci. 2003;91:542–9.Google Scholar
  75. 75.
    Beall CM. Detecting natural selection in high-altitude human populations. Respir Physiol Neurobiol. 2007;158:161–71.PubMedCrossRefGoogle Scholar
  76. 76.
    Wu TY. Chronic mountain sickness on the Qinghai-Tibetan plateau. Chin Med J (Engl). 2005;118:161–8.Google Scholar
  77. 77.
    van Patot MC, Gassmann M. Hypoxia: adapting to high altitude by mutating EPAS-1, the gene encoding HIF-2alpha. High Alt Med Biol. 2011;12:157–67.PubMedCrossRefGoogle Scholar
  78. 78.
    Kayser B, Hoppeler H, Desplanches D, et al. Muscle ultrastructure and biochemistry of lowland Tibetans. J Appl Physiol. 1996;81:419–25.PubMedGoogle Scholar
  79. 79.
    Rosser BW, Hochachka PW. Metabolic capacity of muscle fibers from high-altitude natives. Eur J Appl Physiol Occup Physiol. 1993;67:513–7.PubMedCrossRefGoogle Scholar
  80. 80.
    Kayser B, Hoppeler H, Claassen H, et al. Muscle structure and performance capacity of Himalayan Sherpas. J Appl Physiol. 1991;70:1938–42.PubMedCrossRefGoogle Scholar
  81. 81.
    Marconi C, Marzorati M, Grassi B, et al. Second generation Tibetan lowlanders acclimatize to high altitude more quickly than Caucasians. J Physiol. 2004; 556:661–71.PubMedCrossRefGoogle Scholar
  82. 82.
    Gelfi C, De Palma S, Ripamonti M, et al. New aspects of altitude adaptation in Tibetans: a proteomic approach. FASEB J. 2004;18:612–4.PubMedGoogle Scholar
  83. 83.
    Levine BD. Intermittent hypoxic training: fact and fancy. High Alt Med Biol. 2002;3:177–93.PubMedCrossRefGoogle Scholar
  84. 84.
    Bonetti DL, Hopkins WG. Sea-level exercise performance following adaptation to hypoxia: a meta-analysis. Sports Med. 2009;39:107–27.PubMedCrossRefGoogle Scholar
  85. 85.
    Stray-Gundersen J, Levine BD. Live high, train low at natural altitude. Scand J Med Sci Sports. 2008;18 Suppl 1:21–8.PubMedCrossRefGoogle Scholar
  86. 86.
    Desplanches D, Hoppeler H, Linossier MT, et al. Effects of training in normoxia and normobaric hypoxia on human muscle ultrastructure. Pflugers Arch. 1993;425:263–7.PubMedCrossRefGoogle Scholar
  87. 87.
    Hoppeler H, Klossner S, Vogt M. Training in hypoxia and its effects on skeletal muscle tissue. Scand J Med Sci Sports. 2008;18 Suppl 1:38–49.PubMedCrossRefGoogle Scholar
  88. 88.
    Hoppeler H, Vogt M. Hypoxia training for sea-level performance. Training high-living low. Adv Exp Med Biol. 2001;502:61–73.PubMedCrossRefGoogle Scholar
  89. 89.
    Mounier R, Pialoux V, Roels B, et al. Effect of intermittent hypoxic training on HIF gene expression in human skeletal muscle and leukocytes. Eur J Appl Physiol. 2009;105:515–24.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of AnatomyUniversity of BernBern 9Switzerland

Personalised recommendations