Metabolic basis to Sherpa altitude adaptation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 24; pp. 6382 - 6387
• Main Authors: Horscroft, James A., Kotwica, Aleksandra O., Laner, Verena, West, James A., Hennis, Philip J., Levett, Denny Z. H., Howard, David J., Fernandez, Bernadette O., Burgess, Sarah L., Ament, Zsuzsanna, Gilbert-Kawai, Edward T., Vercueil, André, Landis, Blaine D., Mitchell, Kay, Mythen, Monty G., Branco, Cristina, Johnson, Randall S., Feelisch, Martin, Montgomery, Hugh E., Griffin, Julian L., Grocott, Michael P. W., Gnaiger, Erich, Martin, Daniel S., Murray, Andrew J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 13-06-2017
• Series: From the Cover
• Subjects: Adaptation; Adaptation, Physiological - genetics; Adult; Altitude; Ascent; Atmospheric Pressure; Biological Sciences; Citric Acid Cycle; Energy Metabolism; Ethnic Groups - genetics; Fatty acids; Fatty Acids - metabolism; Female; Gene Frequency; Glucose - metabolism; Glycolysis; High altitude; Human populations; Humans; Hypoxia; Hypoxia - genetics; Hypoxia - metabolism; Hypoxia - physiopathology; Male; Medicin och hälsovetenskap; Metabolism; Minority & ethnic groups; Mitochondria, Muscle - metabolism; Muscle, Skeletal - metabolism; Nepal; Nitric Oxide - blood; Oxidation; Oxidative Phosphorylation; Oxidative Stress; Oxygen; Oxygen Consumption; Polymorphism, Single Nucleotide; PPAR alpha - genetics; PPAR alpha - metabolism; Skeletal muscle; Tibet - ethnology; Himalaya Mountains; altitude; hypoxia; metabolism; skeletal muscle; mitochondria
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1700527114

The Himalayan Sherpas, a human population of Tibetan descent, are highly adapted to life in the hypobaric hypoxia of high altitude. Mechanisms involving enhanced tissue oxygen delivery in comparison to Lowlander populations have been postulated to play a role in such adaptation. Whether differences in tissue oxygen utilization (i.e., metabolic adaptation) underpin this adaptation is not known, however. We sought to address this issue, applying parallel molecular, biochemical, physiological, and genetic approaches to the study of Sherpas and native Lowlanders, studied before and during exposure to hypobaric hypoxia on a gradual ascent to Mount Everest Base Camp (5,300 m). Compared with Lowlanders, Sherpas demonstrated a lower capacity for fatty acid oxidation in skeletal muscle biopsies, along with enhanced efficiency of oxygen utilization, improved muscle energetics, and protection against oxidative stress. This adaptation appeared to be related, in part, to a putatively advantageous allele for the peroxisome proliferator-activated receptor A (PPARA) gene, which was enriched in the Sherpas compared with the Lowlanders. Our findings suggest that metabolic adaptations underpin human evolution to life at high altitude, and could have an impact upon our understanding of human diseases in which hypoxia is a feature.