Metabolic Adaptations to Life at High-Altitude: Evolved Increases in Oxidative Capacity Across Many Skeletal Muscles in High-Altitude Deer Mice, Peromyscus maniculatus

Abstract

The cold and hypoxic conditions at high altitude necessitate high metabolic O2 demands to support thermogenesis while hypoxia reduces O2 availability. Skeletal muscles play key roles in thermogenesis, but our appreciation of muscle plasticity and adaptation at high altitude has been hindered by past emphasis on only a small number of muscles. We examined this issue in deer mice (Peromyscus maniculatus). Mice derived from both high-altitude and low-altitude populations were born and raised in captivity and then exposed as adults to normoxia or hypobaric hypoxia (12 kPa O2 for 6-8 weeks). Maximal activities of citrate synthase (CS), cytochrome c oxidase (COX), β-hydroxyacyl-CoA dehydrogenase (HOAD), hexokinase (HK), pyruvate kinase (PK), and lactate dehydrogenase (LDH) were measured in 20 muscles involved in shivering, locomotion, body posture, ventilation, and mastication. Principal components analysis revealed an overall difference in muscle phenotype between populations but no effect of hypoxia acclimation. High-altitude mice had greater activities of mitochondrial enzymes and/or lower activities of PK/LDH across many (but not all) respiratory, locomotory, and postural muscles compared to low-altitude mice. In contrast, chronic hypoxia exposure had very few effects on metabolic phenotype across muscles. Further examination of CS in the gastrocnemius showed that population differences in enzyme activity stemmed from differences in protein abundance and mRNA expression, but not from population differences in CS amino acid sequence. Overall, our results suggest that evolved increases in oxidative capacity across many skeletal muscles, at least partially driven by differences in transcriptional regulation, may contribute to high-altitude adaptation in deer mice.