Abstract
Skeletal muscle plays a central role in regulating glucose uptake and body metabolism; however, highland hypoxia is a severe challenge to aerobic metabolism in small endotherms. Therefore, understanding the physiological and genetic convergence of muscle hypoxia tolerance has a potential broad range of medical implications. Here we report and experimentally validate a common physiological mechanism across multiple high-altitude songbirds that improvement in insulin sensitivity contributes to glucose homeostasis, low oxygen consumption, and relative activity, and thus increases body weight. By contrast, low-altitude songbirds exhibit muscle loss, glucose intolerance, and increase energy expenditures under hypoxia. This adaptive mechanism is attributable to convergent missense mutations in the BNIP3L gene, and METTL8 gene that activates MEF2C expression in highlanders, which in turn increases hypoxia tolerance. Together, our findings from wild high-altitude songbirds suggest convergent physiological and genetic mechanisms of skeletal muscle in hypoxia resistance, which highlights the potentially medical implications of hypoxia-related metabolic diseases.
Highlights
Hypoxia, including ambient hypoxia [1] and pathological hypoxia [2], induces metabolic alterations, muscle loss and insulin resistance [3,4,5]
Hypoxia resulting from the low barometric pressure is a significantly severe challenge to aerobic exercise and thermogenesis in small endotherms, because a high rate of O2 flux should be concurrently sustained to thermogenesis in cold temperature [6]
Considering muscle fiber-type transition when ascending to high altitudes in mammals [17] and a greater numerical density of oxidative fibres in high-altitude deer mice [18], we Physiological and genetic adaptation to high-altitude hypoxia further compared muscle phenotypic variations among altitudinal species and populations
Summary
Hypoxia, including ambient hypoxia (high-altitude exposure) [1] and pathological hypoxia (diseases) [2], induces metabolic alterations, muscle loss and insulin resistance [3,4,5]. The physiological and genetic changes in skeletal muscles supporting hypoxia resistance are poorly understood, for high-altitude songbirds. A growing body of literature has shown convergent physiological and genetic adaptations to high elevations across variant species. Convergent gene expression and genetic mechanisms for hypoxia adaptation have been elucidated in a number of mammals [11], birds [12], reptiles [13], and amphibians [14]. Whether convergent gene expression shifts or mutants for hypoxia adaptation drive a similar physiology change and subsequently a morphological phenotype in whole organisms remains unclear. We report and experimentally validate using RNA interference in vivo a convergent mechanism that improves insulin sensitivity based on natural selection of standing genetic variations are essential to muscle hypoxia resistance in high-altitude songbirds, which provides novel and valuable insights into understanding vertebrate hypoxia adaptation
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