1932

Abstract

Comparative physiology studies of high-altitude species provide an exceptional opportunity to understand naturally evolved mechanisms of hypoxia resistance. Aerobic capacity (VOmax) is a critical performance trait under positive selection in some high-altitude taxa, and several high-altitude natives have evolved to resist the depressive effects of hypoxia on VOmax. This is associated with enhanced flux capacity through the O transport cascade and attenuation of the maladaptive responses to chronic hypoxia that can impair O transport. Some highlanders exhibit elevated rates of carbohydrate oxidation during exercise, taking advantage of its high ATP yield per mole of O. Certain highland native animals have also evolved more oxidative muscles and can sustain high rates of lipid oxidation to support thermogenesis. The underlying mechanisms include regulatory adjustments of metabolic pathways and to gene expression networks. Therefore, the evolution of hypoxia resistance in high-altitude natives involves integrated functional changes in the pathways for O and substrate delivery and utilization by mitochondria.

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2019-02-10
2024-03-29
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Literature Cited

  1. 1.  Hochachka PW. 1985. Exercise limitations at high altitude: the metabolic problem and search for its solution. Circulation, Respiration, and Metabolism: Current Comparative Approaches R Gilles 240–49 Berlin/Heidelberg: Springer
    [Google Scholar]
  2. 2.  Baker PT. 1978. IBP high-altitude research: development and strategies. The Biology of High-Altitude People PT Baker 1–16 Cambridge, UK: Cambridge Univ. Press
    [Google Scholar]
  3. 3.  Monge CC, León-Velarde FF 1991. Physiological adaptation to high altitude: oxygen transport in mammals and birds. Physiol. Rev. 71:1135–72
    [Google Scholar]
  4. 4.  Gilbert-Kawai ET, Milledge JS, Grocott MPW, Martin DS 2014. King of the mountains: Tibetan and Sherpa physiological adaptations for life at high altitude. Physiology 29:388–402
    [Google Scholar]
  5. 5.  Simonson TS. 2015. Altitude adaptation: a glimpse through various lenses. High Alt. Med. Biol. 16:125–37
    [Google Scholar]
  6. 6.  Bigham AW. 2016. Genetics of human origin and evolution: high-altitude adaptations. Curr. Opin. Genet. Dev. 41:8–13
    [Google Scholar]
  7. 7.  Beall CM. 2014. Adaptation to high altitude: phenotypes and genotypes. Annu. Rev. Anthropol. 43:251–72
    [Google Scholar]
  8. 8.  Moore LG. 2017. Measuring high-altitude adaptation. J. Appl. Physiol. 123:1371–85
    [Google Scholar]
  9. 9.  Azad P, Stobdan T, Zhou D, Hartley I, Akbari A et al. 2017. High-altitude adaptation in humans: from genomics to integrative physiology. J. Mol. Med. 95:1269–82
    [Google Scholar]
  10. 10.  Moritz C, Patton JL, Conroy CJ, Parra JL, White GC, Beissinger SR 2008. Impact of a century of climate change on small-mammal communities in Yosemite National Park, USA. Science 322:261–64
    [Google Scholar]
  11. 11.  Guo Q, Kelt DA, Sun Z, Liu H, Hu L et al. 2013. Global variation in elevational diversity patterns. Sci. Rep. 3:200–7
    [Google Scholar]
  12. 12.  Hall FG, Dill DB, Barron ES 1936. Comparative physiology in high altitudes. J. Cell. Comp. Physiol. 8:301–13
    [Google Scholar]
  13. 13.  Lenfant C. 1973. High altitude adaptation in mammals. Am. Zool. 13:447–56
    [Google Scholar]
  14. 14.  Snyder LR. 1985. Low P50 in deer mice native to high altitude. J. Appl. Physiol. 58:193–99
    [Google Scholar]
  15. 15.  Hayes JP. 1989. Altitudinal and seasonal effects on aerobic metabolism of deer mice. J. Comp. Physiol. B 159:453–59
    [Google Scholar]
  16. 16.  Hayes JP, O'Connor CS 1999. Natural selection on thermogenic capacity of high-altitude deer mice. Evolution 53:1280–87
    [Google Scholar]
  17. 17.  Nespolo RF, Opazo JC, Rosenmann M, Bozinovic F 1999. Thermal acclimation, maximum metabolic rate, and nonshivering thermogenesis of Phyllotis xanthopygus (Rodentia) in the Andes mountains. J. Mammal. 80:742–48
    [Google Scholar]
  18. 18.  Sears MW, Hayes JP, O'Connor CS, Geluso K, Sendinger JS 2006. Individual variation in thermogenic capacity affects above-ground activity of high-altitude deer mice. Funct. Ecol. 20:97–104
    [Google Scholar]
  19. 19.  Hayes JP. 1989. Field and maximal metabolic rates of deer mice (Peromyscus maniculatus) at low and high altitudes. Physiol. Zool. 62:732–44
    [Google Scholar]
  20. 20.  Scholander PF. 1955. Evolution of climatic adaptation in homeotherms. Evolution 9:15–26
    [Google Scholar]
  21. 21.  Cheviron ZA, Bachman GC, Connaty AD, McClelland GB, Storz JF 2012. Regulatory changes contribute to the adaptive enhancement of thermogenic capacity in high-altitude deer mice. PNAS 109:8635–40
    [Google Scholar]
  22. 22.  Schippers M-P, Ramirez O, Arana M, Pinedo-Bernal P, McClelland GB 2012. Increase in carbohydrate utilization in high-altitude Andean mice. Curr. Biol. 22:2350–54
    [Google Scholar]
  23. 23.  Natarajan C, Inoguchi N, Weber RE, Fago A, Moriyama H, Storz JF 2013. Epistasis among adaptive mutations in deer mouse hemoglobin. Science 340:1324–27
    [Google Scholar]
  24. 24.  Shirkey NJ, Hammond KA 2014. The relationship between cardiopulmonary size and aerobic performance in adult deer mice at high altitude. J. Exp. Biol. 217:3758–64
    [Google Scholar]
  25. 25.  Lui MA, Mahalingam S, Patel P, Connaty AD, Ivy CM et al. 2015. High-altitude ancestry and hypoxia acclimation have distinct effects on exercise capacity and muscle phenotype in deer mice. Am. J. Physiol. 308:R779–91
    [Google Scholar]
  26. 26.  Lau DS, Connaty AD, Mahalingam S, Wall N, Cheviron ZA et al. 2017. Acclimation to hypoxia increases carbohydrate use during exercise in high-altitude deer mice. Am. J. Physiol. 312:R400–11
    [Google Scholar]
  27. 27.  Tate KB, Ivy CM, Velotta JP, Storz JF, McClelland GB et al. 2017. Circulatory mechanisms underlying adaptive increases in thermogenic capacity in high-altitude deer mice. J. Exp. Biol. 220:3616–20
    [Google Scholar]
  28. 28.  Storz JF, Scott GR, Cheviron ZA 2010. Phenotypic plasticity and genetic adaptation to high-altitude hypoxia in vertebrates. J. Exp. Biol. 213:4125–36
    [Google Scholar]
  29. 29.  Swenson ER, Bärtsch P 2014. High Altitude: Human Adaptation to Hypoxia New York: Springer
  30. 30.  Brutsaert T. 2016. Why are high altitude natives so strong at high altitude? Nature versus nurture: genetic factors versus growth and development. Adv. Exp. Med. Biol. 903:101–12
    [Google Scholar]
  31. 31.  Storz JF. 2016. Hemoglobin-oxygen affinity in high-altitude vertebrates: is there evidence for an adaptive trend?. J. Exp. Biol. 219:3190–203
    [Google Scholar]
  32. 32.  Ivy CM, Scott GR 2017. Control of breathing and ventilatory acclimatization to hypoxia in deer mice native to high altitudes. Acta Physiol 221:266–82
    [Google Scholar]
  33. 33.  Cheviron ZA, Connaty AD, McClelland GB, Storz JF 2014. Functional genomics of adaptation to hypoxic cold-stress in high-altitude deer mice: transcriptomic plasticity and thermogenic performance. Evolution 68:48–62
    [Google Scholar]
  34. 34.  Scott GR, Elogio TS, Lui MA, Storz JF, Cheviron ZA 2015. Adaptive modifications of muscle phenotype in high-altitude deer mice are associated with evolved changes in gene regulation. Mol. Biol. Evol. 32:1962–76
    [Google Scholar]
  35. 35.  Velotta JP, Jones J, Wolf CJ, Cheviron ZA 2016. Transcriptomic plasticity in brown adipose tissue contributes to an enhanced capacity for non-shivering thermogenesis in deer mice. Mol. Ecol. 25:122870–86
    [Google Scholar]
  36. 36.  Dalziel AC, Rogers SM, Schulte PM 2009. Linking genotypes to phenotypes and fitness: how mechanistic biology can inform molecular ecology. Mol. Ecol. 18:4997–5017
    [Google Scholar]
  37. 37.  Garland T, Adolph SC 1991. Physiological differentiation of vertebrate populations. Annu. Rev. Ecol. Syst. 22:193–228
    [Google Scholar]
  38. 38.  Segrem NP, Hart JS 1967. Oxygen supply and performance in Peromyscus: comparisons of exercise with cold exposure. Can. J. Physiol. Pharmacol. 45:543–49
    [Google Scholar]
  39. 39.  Calbet JALJ, Boushel RR, Radegran GG, Sondergaard HH et al. 2003. Why is VO2max after altitude acclimatization still reduced despite normalization of arterial O2 content?. Am. J. Physiol. 284:R304–16
    [Google Scholar]
  40. 40.  Taylor CR, Weibel ER, Weber JM, Vock R, Hoppeler H et al. 1996. Design of the oxygen and substrate pathways. I. Model and strategy to test symmorphosis in a network structure. J. Exp. Biol. 199:1643–49
    [Google Scholar]
  41. 41.  Chappell MA, Snyder LR 1984. Biochemical and physiological correlates of deer mouse alpha-chain hemoglobin polymorphisms. PNAS 81:5484–88
    [Google Scholar]
  42. 42.  Hochachka PW. 1998. Mechanism and evolution of hypoxia-tolerance in humans. J. Exp. Biol. 201:1243–54
    [Google Scholar]
  43. 43.  McClelland GB, Hochachka PW, Weber JM 1998. Carbohydrate utilization during exercise after high-altitude acclimation: a new perspective. PNAS 95:10288–93
    [Google Scholar]
  44. 44.  Martin D, O'Kroy J 1992. Effects of acute hypoxia on the VO2max of trained and untrained subjects. J. Sports Sci. 11:37–42
    [Google Scholar]
  45. 45.  McClelland GB, Lyons SA, Robertson CE 2017. Fuel use in mammals: conserved patterns and evolved strategies for aerobic locomotion and thermogenesis. Integr. Comp. Biol. 57:231–39
    [Google Scholar]
  46. 46.  Cannon B, Nedergaard J 2004. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84:1277–359
    [Google Scholar]
  47. 47.  Cannon B, Nedergaard J 2011. Nonshivering thermogenesis and its adequate measurement in metabolic studies. J. Exp. Biol. 214:2242–53
    [Google Scholar]
  48. 48.  Chappell MA, Hammond KA 2004. Maximal aerobic performance of deer mice in combined cold and exercise challenges. J. Comp. Physiol. B 174:41–48
    [Google Scholar]
  49. 49.  Armstrong RB, Essén-Gustavsson B, Hoppeler H, Jones JH, Kayar SR et al. 1992. O2 delivery at VO2max and oxidative capacity in muscles of standardbred horses. J. Appl. Physiol. 73:2274–82
    [Google Scholar]
  50. 50.  Weibel ER, Hoppeler H 2005. Exercise-induced maximal metabolic rate scales with muscle aerobic capacity. J. Exp. Biol. 208:1635–44
    [Google Scholar]
  51. 51.  Van Sant MJ, Hammond KA 2008. Contribution of shivering and nonshivering thermogenesis to thermogenic capacity for the deer mouse (Peromyscus maniculatus). Physiol. Biochem. Zool. 81:605–11
    [Google Scholar]
  52. 52.  Cheviron ZA, Bachman GC, Storz JF 2013. Contributions of phenotypic plasticity to differences in thermogenic performance between highland and lowland deer mice. J. Exp. Biol. 216:1160–66
    [Google Scholar]
  53. 53.  Beaudry JL, McClelland GB 2010. Thermogenesis in CD-1 mice after combined chronic hypoxia and cold acclimation. Comp. Biochem. Physiol. B 157:301–9
    [Google Scholar]
  54. 54.  Conley KE, Porter WP 1986. Heat loss from deer mice (Peromyscus): evaluation of seasonal limits to thermoregulation. J. Exp. Biol. 126:249–69
    [Google Scholar]
  55. 55.  Killen SS, Calsbeek R, Williams TD 2017. The ecology of exercise: mechanisms underlying individual variation in behavior, activity, and performance: an introduction to symposium. Integr. Comp. Biol. 57:2185–94
    [Google Scholar]
  56. 56.  Weibel ER, Taylor CR, Hoppeler H 1991. The concept of symmorphosis: a testable hypothesis of structure-function relationship. PNAS 88:10357–61
    [Google Scholar]
  57. 57.  Gonzalez NC, Kirkton SD, Howlett RA, Britton SL, Koch LG et al. 2006. Continued divergence in VO2max of rats artificially selected for running endurance is mediated by greater convective blood O2 delivery. J. Appl. Physiol. 101:1288–96
    [Google Scholar]
  58. 58.  Henderson KK, Wagner H, Favret F, Britton SL, Koch LG et al. 2002. Determinants of maximal O2 uptake in rats selectively bred for endurance running capacity. J. Appl. Physiol. 93:1265–74
    [Google Scholar]
  59. 59.  Maina JN, McCracken KG, Chua B, York JM, Milsom WK 2017. Morphological and morphometric specializations of the lung of the Andean goose, Chloephaga melanoptera: a lifelong high-altitude resident. PLOS ONE 12:e0174395
    [Google Scholar]
  60. 60.  Pearson OP, Pearson A 1976. A stereological analysis of the ultrastructure of the lungs of wild mice living at low and high altitude. J. Morphol. 150:359–68
    [Google Scholar]
  61. 61.  Hsia CC, Carbayo JJ, Yan X, Bellotto DJ 2005. Enhanced alveolar growth and remodeling in Guinea pigs raised at high altitude. Respir. Physiol. Neurobiol. 147:105–15
    [Google Scholar]
  62. 62.  Hsia CCW, Johnson RL, McDonough P, Dane DM, Hurst MD et al. 2007. Residence at 3,800-m altitude for 5 mo in growing dogs enhances lung diffusing capacity for oxygen that persists at least 2.5 years. J. Appl. Physiol. 102:1448–55
    [Google Scholar]
  63. 63.  Burri PH, Weibel ER 1971. Morphometric estimation of pulmonary diffusion capacity. II. Effect of Po2 on the growing lung adaption of the growing rat lung to hypoxia and hyperoxia. Respir. Physiol. 11:247–64
    [Google Scholar]
  64. 64.  Scott GR, Schulte PM, Egginton S, Scott ALM, Richards JG, Milsom WK 2011. Molecular evolution of cytochrome c oxidase underlies high-altitude adaptation in the bar-headed goose. Mol. Biol. Evol. 28:351–63
    [Google Scholar]
  65. 65.  York JM, Scadeng M, McCracken KG, Milsom WK 2018. Respiratory mechanics and morphology of Tibetan and Andean high-altitude geese with divergent life histories. J. Exp. Biol. 221:jeb170738
    [Google Scholar]
  66. 66.  Lechner AJ. 1977. Metabolic performance during hypoxia in native and acclimated pocket gophers. J. Appl. Physiol. 43:965–70
    [Google Scholar]
  67. 67.  Natarajan C, Hoffmann FG, Weber RE, Fago A, Witt CC, Storz JF 2016. Predictable convergence in hemoglobin function has unpredictable molecular underpinnings. Science 354:336–39
    [Google Scholar]
  68. 68.  Weber RE. 2007. High-altitude adaptations in vertebrate hemoglobins. Respir. Physiol. Neurobiol. 158:132–42
    [Google Scholar]
  69. 69.  Storz JF, Moriyama H 2008. Mechanisms of hemoglobin adaptation to high altitude hypoxia. High Alt. Med. Biol. 9:148–57
    [Google Scholar]
  70. 70.  Scott GR, Milsom WK 2007. Control of breathing and adaptation to high altitude in the bar-headed goose. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293:R379–R91
    [Google Scholar]
  71. 71.  Chen QH, Ge RL, Wang XZ, Chen HX, Wu TY et al. 1997. Exercise performance of Tibetan and Han adolescents at altitudes of 3,417 and 4,300 m. J. Appl. Physiol. 83:661–67
    [Google Scholar]
  72. 72.  Ge R-L, Lun G-WH, Chen Q-H, Li H-L, Gen D et al. 1995. Comparisons of oxygen transport between Tibetan and Han residents at moderate altitude. Wilderness Environ. Med. 6:391–400
    [Google Scholar]
  73. 73.  Kayser B, Hoppeler H, Claassen H, Cerretelli P 1991. Muscle structure and performance capacity of Himalayan Sherpas. J. Appl. Physiol. 70:1938–42
    [Google Scholar]
  74. 74.  Mathieu-Costello O, Agey PJ, Wu L, Szewczak JM, MacMillen RE 1998. Increased fiber capillarization in flight muscle of finch at altitude. Respir. Physiol. 111:189–99
    [Google Scholar]
  75. 75.  Scott GR, Egginton S, Richards JG, Milsom WK 2009. Evolution of muscle phenotype for extreme high altitude flight in the bar-headed goose. Proc. R. Soc. Lond. B 276:3645–53
    [Google Scholar]
  76. 76.  Mahalingam S, McClelland GB, Scott GR 2017. Evolved changes in the intracellular distribution and physiology of muscle mitochondria in high-altitude native deer mice. J. Physiol. 595:144785–801
    [Google Scholar]
  77. 77.  Simonson TS, Yang Y, Huff CD, Yun H, Qin G et al. 2010. Genetic evidence for high-altitude adaptation in Tibet. Science 329:72–75
    [Google Scholar]
  78. 78.  Wei C, Wang H, Liu G, Zhao F, Kijas JW et al. 2016. Genome-wide analysis reveals adaptation to high altitudes in Tibetan sheep. Sci. Rep. 6:26770
    [Google Scholar]
  79. 79.  Qu Y, Zhao H, Han N, Zhou G, Song G et al. 2013. Ground tit genome reveals avian adaptation to living at high altitudes in the Tibetan plateau. Nat. Commun. 4:2071
    [Google Scholar]
  80. 80.  Dempsey JA, Morgan BJ 2015. Humans in hypoxia: a conspiracy of maladaptation?!. Physiology 30:304–16
    [Google Scholar]
  81. 81.  Ivy CM, Scott GR 2015. Control of breathing and the circulation in high-altitude mammals and birds. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 186:66–74
    [Google Scholar]
  82. 82.  Monge CC, Arregui A, Léon-Velarde F 1992. Pathophysiology and epidemiology of chronic mountain sickness. Int. J. Sports Med. 13:S79–81
    [Google Scholar]
  83. 83.  Rhodes J. 2005. Comparative physiology of hypoxic pulmonary hypertension: historical clues from brisket disease. J. Appl. Physiol. 98:1092–100
    [Google Scholar]
  84. 84.  Shimoda LA, Laurie SS 2014. HIF and pulmonary vascular responses to hypoxia. J. Appl. Physiol. 116:867–74
    [Google Scholar]
  85. 85.  Sylvester JT, Shimoda LA, Aaronson PI, Ward JPT 2012. Hypoxic pulmonary vasoconstriction. Physiol. Rev. 92:367–520
    [Google Scholar]
  86. 86.  Groves BM, Droma T, Sutton JR, McCullough RG, McCullough RE et al. 1993. Minimal hypoxic pulmonary hypertension in normal Tibetans at 3,658 m. J. Appl. Physiol. 74:312–18
    [Google Scholar]
  87. 87.  Ge RL, Kubo K, Kobayashi T, Sekiguchi M, Honda T 1998. Blunted hypoxic pulmonary vasoconstrictive response in the rodent Ochotona curzoniae (pika) at high altitude. Am. J. Physiol. Heart Circ. Physiol. 274:H1792–99
    [Google Scholar]
  88. 88.  Harris P, Heath D, Smith P, Williams DR, Ramirez A et al. 1982. Pulmonary circulation of the llama at high and low altitudes. Thorax 37:38–45
    [Google Scholar]
  89. 89.  Velotta JP, Ivy CM, Wolf CJ, Scott GR, Cheviron ZA 2018. Maladaptive phenotypic plasicity in cardiac muscle growth is suppressed in high-altitude deer mice. Evolution In press
  90. 90.  Zhang XJ, Zhang P, Li H 2015. Interferon regulatory factor signalings in cardiometabolic diseases. Hypertension 66:222–47
    [Google Scholar]
  91. 91.  Beall CM, Reichsman AB 1984. Hemoglobin levels in a Himalayan high altitude population. Am. J. Phys. Anthropol. 63:301–6
    [Google Scholar]
  92. 92.  Black CP, Tenney SM 1980. Oxygen transport during progressive hypoxia in high altitude and sea level waterfowl. Respir. Physiol. 39:217–39
    [Google Scholar]
  93. 93.  Siebenmann C, Robach P, Lundby C 2017. Regulation of blood volume in lowlanders exposed to high altitude. J. Appl. Physiol. 123:957–66
    [Google Scholar]
  94. 94.  Winslow RM, Monge CC, Brown EG, Klein HG, Sarnquist F et al. 1985. Effects of hemodilution on O2 transport in high-altitude polycythemia. J. Appl. Physiol. 59:1495–502
    [Google Scholar]
  95. 95.  Greer SN, Metcalf JL, Wang Y, Ohh M 2012. The updated biology of hypoxia-inducible factor. EMBO J 31:2448–60
    [Google Scholar]
  96. 96.  Prabhakar NR, Semenza GL 2012. Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2. Physiol. Rev. 92:967–1003
    [Google Scholar]
  97. 97.  Song S, Yao N, Yang M, Liu X, Dong K et al. 2016. Exome sequencing reveals genetic differentiation due to high-altitude adaptation in the Tibetan cashmere goat (Capra hircus). BMC Genom 17:122
    [Google Scholar]
  98. 98.  Beall CM, Cavalleri GL, Deng L, Elston RC, Gao Y et al. 2010. Natural selection on EPAS1 (HIF2α) associated with low hemoglobin concentration in Tibetan highlanders. PNAS 107:11459–64
    [Google Scholar]
  99. 99.  Cowburn AS, Crosby A, Macias D, Branco C, Colaço RDDR et al. 2016. HIF2α–arginase axis is essential for the development of pulmonary hypertension. PNAS 113:8801–6
    [Google Scholar]
  100. 100.  Hainsworth R, Drinkhill MJ 2007. Cardiovascular adjustments for life at high altitude. Respir. Physiol. Neurobiol. 158:204–11
    [Google Scholar]
  101. 101.  Bernardi L, Passino C, Spadacini G, Calciati A, Robergs R et al. 1998. Cardiovascular autonomic modulation and activity of carotid baroreceptors at altitude. Clin. Sci. 95:565–73
    [Google Scholar]
  102. 102.  Calbet JA. 2003. Chronic hypoxia increases blood pressure and noradrenaline spillover in healthy humans. J. Physiol. 551:379–86
    [Google Scholar]
  103. 103.  Ivy CM, Scott GR 2017. Ventilatory acclimatization to hypoxia in mice: methodological considerations. Respir. Physiol. Neurobiol. 235:95–103
    [Google Scholar]
  104. 104.  León-Velarde F, Richalet JP, Chavez JC, Kacimi R, Rivera-Chira M et al. 1996. Hypoxia- and normoxia-induced reversibility of autonomic control in Andean guinea pig heart. J. Appl. Physiol. 81:2229–34
    [Google Scholar]
  105. 105.  Pichon A, Zhenzhong B, Marchant D, Jin G, Voituron N et al. 2013. Cardiac adaptation to high altitude in the plateau pika (Ochotona curzoniae). Physiol. Rep. 1:e00032
    [Google Scholar]
  106. 106.  Giussani DA, Riquelme RA, Moraga FA, McGarrigle HH, Gaete CR et al. 1996. Chemoreflex and endocrine components of cardiovascular responses to acute hypoxemia in the llama fetus. Am. J. Physiol. Regul. Integr. Comp. Physiol. 271:R73–83
    [Google Scholar]
  107. 107.  Moraga FA, Reyes RV, Herrera EA, Riquelme RA, Ebensperger G et al. 2011. Role of the α-adrenergic system in femoral vascular reactivity in neonatal llamas and sheep: a comparative study between highland and lowland species. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301:R1153–56
    [Google Scholar]
  108. 108.  Erzurum SC, Ghosh S, Janocha AJ, Xu W, Bauer S et al. 2007. Higher blood flow and circulating NO products offset high-altitude hypoxia among Tibetans. PNAS 104:17593–98
    [Google Scholar]
  109. 109.  Sanhueza EM, Riquelme RA, Herrera EA, Giussani DA, Blanco CE et al. 2005. Vasodilator tone in the llama fetus: the role of nitric oxide during normoxemia and hypoxemia. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289:R776–83
    [Google Scholar]
  110. 110.  Brand MD. 2005. The efficiency and plasticity of mitochondrial energy transduction. Biochem. Soc. Trans. 33:897–904
    [Google Scholar]
  111. 111.  Welch KC, Altshuler DL, Suarez RK 2007. Oxygen consumption rates in hovering hummingbirds reflect substrate-dependent differences in P/O ratios: carbohydrate as a ‘premium fuel.’. J. Exp. Biol 210:2146–53
    [Google Scholar]
  112. 112.  Roberts AC, Butterfield GE, Cymerman A, Reeves JT, Wolfel E, et al. 1996. Acclimation to 4,300-m altitude decreases reliance on fat as a substrate. J. Appl. Physiol. 81:1762–71
    [Google Scholar]
  113. 113.  Roberts AC, Reeves JT, Butterfield GE, Mazzeo RS, Sutton JR et al. 1996. Altitude and β-blockade augment glucose utilization during submaximal exercise. J. Appl. Physiol. 80:605–15
    [Google Scholar]
  114. 114.  Young PM, Sutton JR, Green HJ, Reeves JT, Rock PB et al. 1992. Operation Everest II: metabolic and hormonal responses to incremental exercise to exhaustion. J. Appl. Physiol. 73:2574–79
    [Google Scholar]
  115. 115.  Brooks GA, Butterfield GE, Wolfe RR, Groves BM, Mazzeo RS et al. 1991. Increased dependence on blood glucose after acclimatization to 4,300 m. J. Appl. Physiol. 70:919–27
    [Google Scholar]
  116. 116.  Schippers M-P, LeMoine CMR, McClelland GB 2014. Patterns of fuel use during locomotion in mammals revisited: the importance of aerobic scope. J. Exp. Biol. 217:3193–96
    [Google Scholar]
  117. 117.  Brooks GA, Mercier J 1994. Balance of carbohydrate and lipid utilization during exercise: The “crossover” concept. J. Appl. Physiol. 76:2253–61
    [Google Scholar]
  118. 118.  Braun B, Mawson JT, Muza SR, Dominick SB, Brooks GA et al. 2000. Women at altitude: carbohydrate utilization during exercise at 4,300 m.. J. Appl. Physiol. 88:246–56
    [Google Scholar]
  119. 119.  Braun B. 2008. Effects of high altitude on substrate use and metabolic economy. Med. Sci. Sports Exerc. 40:1495–500
    [Google Scholar]
  120. 120.  Lundby C, van Hall G 2002. Substrate utilization in sea level residents during exercise in acute hypoxia and after 4 weeks of acclimatization to 4100 m. Acta Physiol. Scand. 176:195–201
    [Google Scholar]
  121. 121.  McClelland GB, Hochachka PW, Weber JM 1999. Effect of high-altitude acclimation on NEFA turnover and lipid utilization during exercise in rats. Am. J. Physiol. 277:E1095–102
    [Google Scholar]
  122. 122.  Hochachka PW, Clark CM, Brown WD, Stanley C, Stone CK et al. 1994. The brain at high altitude: hypometabolism as a defence against chronic hypoxia. J. Cereb. Blood Flow Metab. 14:671–79
    [Google Scholar]
  123. 123.  Hochachka PW, Clark CM, Holden JE, Stanley C, Ugurbil K, Menon RS 1996. 31P magnetic resonance spectroscopy of the Sherpa heart: a phosphocreatine/adenosine triphosphate signature of metabolic defence against hypoxia. PNAS 93:1215–20
    [Google Scholar]
  124. 124.  Weber JM, Haman F 2005. Fuel selection in shivering humans. Acta Physiol. Scand. 184:319–29
    [Google Scholar]
  125. 125.  Vaillencourt E, Haman F, Weber JM 2009. Fuel selection in Wistar rats exposed to cold: shivering thermogenesis diverts fatty acids from re-esterification to oxidation. J. Physiol. 587:4349–59
    [Google Scholar]
  126. 126.  Haman F, Mantha OL, Cheung SS, DuCharme MB, Taber M et al. 2016. Oxidative fuel selection and shivering thermogenesis during a 12- and 24-h cold-survival simulation. J. Appl. Physiol. 120:640–48
    [Google Scholar]
  127. 127.  Wasserman DH. 2009. Four grams of glucose. Am. J. Physiol. 296:E11–21
    [Google Scholar]
  128. 128.  Wasserman DH, Kang L, Ayala JE, Fueger PT, Lee-Young RS 2011. The physiological regulation of glucose flux into muscle in vivo. J. Exp. Biol. 214:254–62
    [Google Scholar]
  129. 129.  Trefts E, Williams AS, Wasserman DH 2015. Exercise and the regulation of hepatic metabolism. Prog. Mol. Biol. Transl. Sci. 135:203–25
    [Google Scholar]
  130. 130.  Picon-Reategui E, Buskirk ER, Baker PT 1970. Blood glucose in high-altitude natives and during acclimatization to altitude. J. Appl. Physiol. 29:560–63
    [Google Scholar]
  131. 131.  Mazzeo RS, Bender PR, Brooks GA, Butterfield GE, Groves BM et al. 1991. Arterial catecholamine responses during exercise with acute and chronic high-altitude exposure. Am. J. Physiol. 261:E419–24
    [Google Scholar]
  132. 132.  Mazzeo RS. 2008. Physiological responses to exercise at altitude: an update. Sports Med 38:1–8
    [Google Scholar]
  133. 133.  Mazzeo RS, Carroll JD, Butterfield GE, Braun B, Rock PB et al. 2001. Catecholamine responses to α-adrenergic blockade during exercise in women acutely exposed to altitude. J. Appl. Physiol. 90:121–26
    [Google Scholar]
  134. 134.  Patel MS, Korotchkina LG 2006. Regulation of the pyruvate dehydrogenase complex. Biochem. Soc. Trans. 34:217–22
    [Google Scholar]
  135. 135.  Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC 2006. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell. Metab. 3:187–97
    [Google Scholar]
  136. 136.  Hochachka PWP, Beatty CLC, Burelle YY, Trump MEM, McKenzie DCD, Matheson GOG 2002. The lactate paradox in human high-altitude physiological performance. News Physiol. Sci. 17:122–26
    [Google Scholar]
  137. 137.  Le Moine CMR, Morash AJ, McClelland GB 2011. Changes in HIF-1α protein, pyruvate dehydrogenase phosphorylation, and activity with exercise in acute and chronic hypoxia. Am. J. Physiol. 301:R1098–104
    [Google Scholar]
  138. 138.  Ge R-L, Simonson TS, Gordeuk V, Prchal JT, McClain DA 2015. Metabolic aspects of high-altitude adaptation in Tibetans. Exp. Physiol. 100:1247–55
    [Google Scholar]
  139. 139.  Blondin DP, Frisch F, Phoenix S, Guérin B, Turcotte ÉE et al. 2017. Inhibition of intracellular triglyceride lipolysis suppresses cold-induced brown adipose tissue metabolism and increases shivering in humans. Cell Metabol 25:438–47
    [Google Scholar]
  140. 140.  Lundsgaard A-M, Fritzen AM, Kiens B 2018. Molecular regulation of fatty acid oxidation in skeletal muscle during aerobic exercise. Trends Endocrin. Metabol. 29:18–30
    [Google Scholar]
  141. 141.  Roberts AC, Butterfield GE, Cymerman A, Reeves JT, Wolfel EE, Brooks GA 1996. Acclimatization to 4,300-m altitude decreases reliance on fat as a substrate. J. Appl. Physiol. 81:1762–71
    [Google Scholar]
  142. 142.  Young AJ, Evans WJ, Cymerman A, Pandolf KB, Knapik JJ, Maher JT 1982. Sparing effect of chronic high-altitude exposure on muscle glycogen utilization. J. Appl. Physiol. 52:857–62
    [Google Scholar]
  143. 143.  Hagenfeldt L. 1975. Turnover of individual free fatty acids in man. Fed. Proc. 34:2246–49
    [Google Scholar]
  144. 144.  Brooks GA. 2016. Energy flux, lactate shuttling, mitochondrial dynamics, and hypoxia. Adv. Exp. Med. Biol. 903:439–55
    [Google Scholar]
  145. 145.  Hargreaves M, Kiens B, Richter EA 1991. Effect of increased plasma free fatty acid concentrations on muscle metabolism in exercising men. J. Appl. Physiol. 70:194–201
    [Google Scholar]
  146. 146.  Sidossis LS, Gastaldelli A, Klein S, Wolfe RR 1997. Regulation of plasma fatty acid oxidation during low- and high-intensity exercise. Am. J. Physiol. 272:E1065–70
    [Google Scholar]
  147. 147.  Templeman NM, Schutz H, Garland T, McClelland GB 2012. Do mice selectively bred for high locomotor activity have a greater reliance on lipids to power submaximal aerobic exercise?. Am. J. Physiol. 303:R101–11
    [Google Scholar]
  148. 148.  McClelland GB. 2004. Fat to the fire: the regulation of lipid oxidation with exercise and environmental stress. Comp. Biochem. Physiol. B 139:443–60
    [Google Scholar]
  149. 149.  Kerner J, Hoppel CL 2005. Carnitine palmitoyltransferase-I and regulation of mitochondrial fatty acid oxidation. Mon. Chem. 136:1311–23
    [Google Scholar]
  150. 150.  Labbé SM, Caron A, Bakan I, Laplante M, Carpentier AC et al. 2015. In vivo measurement of energy substrate contribution to cold-induced brown adipose tissue thermogenesis. FASEB J 29:2046–58
    [Google Scholar]
  151. 151.  Simcox J, Geoghegan G, Maschek JA, Bensard CL, Pasquali M et al. 2017. Global analysis of plasma lipids identifies liver-derived acylcarnitines as a fuel source for brown fat thermogenesis. Cell Metabol 26:509–22
    [Google Scholar]
  152. 152.  McClelland G, Zwingelstein G, Taylor CR, Weber JM 1994. Increased capacity for circulatory fatty acid transport in a highly aerobic mammal. Am. J. Physiol. 266:R1280–86
    [Google Scholar]
  153. 153.  Storz JF, Dubach JM 2004. Natural selection drives altitudinal divergence at the albumin locus in deer mice. Peromyscus maniculatus. Evolution 58:1342–52
    [Google Scholar]
  154. 154.  Weibel ER, Bacigalupe LD, Schmitt B, Hoppeler H 2004. Allometric scaling of maximal metabolic rate in mammals: muscle aerobic capacity as determinant factor. Respir. Physiol. Neurobiol. 140:115–32
    [Google Scholar]
  155. 155.  Schwerzmann K, Hoppeler H, Kayar SR, Weibel ER 1989. Oxidative capacity of muscle and mitochondria: correlation of physiological, biochemical, and morphometric characteristics. PNAS 86:1583–87
    [Google Scholar]
  156. 156.  Jacobs RA, Lundby C 2013. Mitochondria express enhanced quality as well as quantity in association with aerobic fitness across recreationally active individuals up to elite athletes. J. Appl. Physiol. 114:344–50
    [Google Scholar]
  157. 157.  Hepple RT. 2016. Impact of aging on mitochondrial function in cardiac and skeletal muscle. Free Radic. Biol. Med. 98:177–86
    [Google Scholar]
  158. 158.  Gnaiger E. 2009. Capacity of oxidative phosphorylation in human skeletal muscle: new perspectives of mitochondrial physiology. Int. J. Biochem. Cell Biol. 41:1837–45
    [Google Scholar]
  159. 159.  Gnaiger E. 2001. Bioenergetics at low oxygen: dependence of respiration and phosphorylation on oxygen and adenosine diphosphate supply. Respir. Physiol. 128:277–97
    [Google Scholar]
  160. 160.  Gnaiger E, Steinlechner-Maran R, Méndez G, Eberl T, Margreiter R 1995. Control of mitochondrial and cellular respiration by oxygen. J. Bioenerg. Biomembr. 27:583–96
    [Google Scholar]
  161. 161.  Scott GR, Richards JG, Milsom WK 2009. Control of respiration in flight muscle from the high-altitude bar-headed goose and low-altitude birds. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297:R1066–74
    [Google Scholar]
  162. 162.  Hochachka PW, Stanley C, Merkt J, Sumar-Kalinowski J 1983. Metabolic meaning of elevated levels of oxidative enzymes in high altitude adapted animals: an interpretive hypothesis. Respir. Physiol. 52:303–13
    [Google Scholar]
  163. 163.  Kayser B, Hoppeler H, Desplanches D, Marconi C, Broers B, Cerretelli P 1996. Muscle ultrastructure and biochemistry of lowland Tibetans. J. Appl. Physiol. 81:419–25
    [Google Scholar]
  164. 164.  Horscroft JA, Kotwica AO, Laner V, West JA, Hennis PJ et al. 2017. Metabolic basis to Sherpa altitude adaptation. PNAS 114:6382–87
    [Google Scholar]
  165. 165.  Lau GY, Mandic M, Richards JG 2017. Evolution of cytochrome c oxidase in hypoxia tolerant sculpins (Cottidae, Actinopterygii). Mol. Biol. Evol. 34:2153–62
    [Google Scholar]
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