Evolved Mechanisms of Aerobic Performance and Hypoxia Resistance in High-Altitude Natives

Comparative physiology studies of high-altitude species provide an exceptional opportunity to understand naturally evolved mechanisms of hypoxia resistance. Aerobic capacity (VO 2 max) 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 VO 2 max. This is associated with enhanced flux capacity through the O 2 transport cascade and attenuation of the maladaptive responses to chronic hypoxia that can impair O 2 transport. Some highlanders exhibit elevated rates of carbohydrate oxidation during exercise, taking advantage of its high ATP yield per mole of O 2 . 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 2 and substrate delivery and utilization by mitochondria.