Abstract
Fullerton, Zackery S., Benjamin D. McNair, Nicholas A. Marcello, Emily E. Schmitt, and Danielle R. Bruns. Exposure to high altitude promotes loss of muscle mass that is not rescued by metformin. High Alt Med Biol. xx:xxx-xxx, 2022. Background: Exposure to high altitude (HA) causes muscle atrophy. Few therapeutic interventions attenuate muscle atrophy; however, the diabetic drug, metformin (Met), has been suggested as a potential therapeutic to preserve muscle mass with aging and obesity-related atrophy. The purpose of the present study was to test the hypothesis that HA would induce muscle atrophy that could be attenuated by Met. Methods: C57Bl6 male and female mice were exposed to simulated HA (∼5,200 m) for 4 weeks, while control (Con) mice remained at resident altitude (∼2,180 m). Met was administered in drinking water at 200 mg/(kg·day). We assessed muscle mass, myocyte cell size, muscle and body composition, and expression of molecular mediators of atrophy. Results: Mice exposed to HA were leaner and had a smaller hind limb complex (HLC) mass than Con mice. Loss of HLC mass and myocyte size were not attenuated by Met. Molecular markers for muscle atrophy were activated at HA in a sex-dependent manner. While the atrophic regulator, atrogin, was unchanged at HA or with Met, myostatin expression was upregulated at HA. In female mice, Met further stimulated myostatin expression. Conclusions: Although HA exposure resulted in loss of muscle mass, particularly in male mice, Met did not attenuate muscle atrophy. Identification of other interventions to preserve muscle mass during ascent to HA is warranted.
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