ABSTRACT
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.
Subject(s)
Adaptation, Physiological , Altitude , Ethnicity , Hypoxia/metabolism , Adaptation, Physiological/genetics , Adult , Atmospheric Pressure , Citric Acid Cycle , Energy Metabolism , Ethnicity/genetics , Fatty Acids/metabolism , Female , Gene Frequency , Glucose/metabolism , Glycolysis , Humans , Hypoxia/genetics , Hypoxia/physiopathology , Male , Mitochondria, Muscle/metabolism , Muscle, Skeletal/metabolism , Nepal , Nitric Oxide/blood , Oxidative Phosphorylation , Oxidative Stress , Oxygen Consumption , PPAR alpha/genetics , PPAR alpha/metabolism , Polymorphism, Single Nucleotide , Tibet/ethnologyABSTRACT
At the annual Iditarod Race, Alaskan Huskies repeatedly run for up to 8 hours at 16 km/h to complete 1600 km. We previously demonstrated high rates of mitochondrial protein synthesis in Alaskan Huskies, which we suspected allowed rapid remodeling of mitochondrial proteins in response to energetic stress. The purpose of this study was to examine mitochondrial respiration in permeabilized skeletal muscle fibers of Alaskan Huskies in the offseason (Non-raced) and following the 1600 km Iditarod Sled Dog Race (Raced). We hypothesized that compared to Non-raced Huskies, raced Huskies that completed a 1600 km race would have greater mitochondrial respiratory capacities, and improvements in capacities of oxidative phosphorylation (OXPHOS) based on NADH-generating substrates as compared to fatty acids. Using high-resolution respirometry (HRR) we investigated the respiration of permeabilized muscle fibers from Alaskan Huskies. Maximum capacities were 254±26 pmol.s-1.mg-1 for OXPHOS (coupled, P) and 254±37 pmol.s-1.mg-1 for the electron transfer system (ETS; non-coupled, E). After racing respiratory capacities from NADH-linked substrates, but not fat-derived substrates increased. Finally, the OXPHOS to ETS capacity ratio (P/E) increased after racing from 0.90±0.03 to 0.97±0.02. From our previous studies and the current study, we conclude that Alaskan Huskies maintain high mitochondrial protein turnover to facilitate rapid adaptation to environmental extremes and energetic challenges.
