Physiological And Genetic Convergence Supports Hypoxia Resistance In High-Altitude Songbirds

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.Author summaryWe integrate physiological, genomic and functional experimental methods to illustrate the convergent molecular and genetic mechanisms of hypoxia resistance in wild songbirds. We find that highland native songbirds have greater body and muscle mass with an increase in insulin sensitivity and aerobic metabolism comparing to lowland songbirds. Comparative transcriptomes and functional experiments show that MEF2C is a shared overexpression gene in highland songbirds and maintains muscle mass and insulin sensitivity in hypoxia. Genetically, four genes with high genetic divergence between altitudinal tree sparrows have convergent nonsynonymous substitutions in snow finches and three of these are related with hypoxia including HBB, BNIP3L and METTL8. METTL8 may regulate the expression of MEF2C and thus increase muscle hypoxia resistance. These results uncover the physiological and genetic convergence on muscle hypoxia resistance in highland songbirds, and support novel and valuable insights into highland adaptation.