Evolved changes in phenotype across skeletal muscles in deer mice native to high altitude

Authors: GARRETT, EMILY - McMaster University; PRASAD, SRIKRIPA - McMaster University; Schweizer, Rena; MCCLELLAND, GRANT - McMaster University; SCOTT, GRAHAM - McMaster University

Submitted to: American Journal of Physiology - Regulatory Integrative & Comparative Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/9/2024
Publication Date: N/A
Citation: N/A

Interpretive Summary: Oxygen is highly limited in high-altitude environments, yet endothermic animals require it to support heat generation (thermogenesis). We know that some skeletal muscles are important for thermogenesis, yet the role of the majority of skeletal muscles in high-altitude adaptation remains unknown. In this study, we examined muscle phenotypes for 20 muscles involved in shivering, locomotion, body posture, ventilation, and chewing, and measured their differences in deer mice (Peromyscus maniculatus) derived from high- and low-altitude populations, then acclimated to normoxia or hypoxia. We found that high-altitude mice demonstrate evolved changes to their muscle physiology in many muscles across the body. In contrast, hypoxia exposure did not significantly change muscle physiology. We also found that some of these muscle changes are likely due to differences in protein abundance and gene expression, but not changes that alter the structure of the protein. Altogether, this study advances our scientific understanding of high-altitude adaptation and physiology, which has potential applications to human physiology and medicine.

Technical 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), ß-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.