Glutathione peroxidase 1 (GPX1) is an essential regulator of skeletal muscle mass in response to endurance exercise training

Introduction: Glutathione peroxidase 1 (GPX1) is a cytosolic and mitochondrial antioxidant that is ubiquitously expressed in mammalian cells. Our recent proteomic analyses suggest that GPX1 protein is enriched in circulating extracellular vesicles (EVs) obtained from both mice and humans following endurance exercise training (ExerVs). Additional follow up analyses also demonstrated that systemic injection of GPX1-enriched ExerVs promotes beneficial adaptations in skeletal muscle of mice under sedentary conditions or after disuse, including increased Type 1 fiber size, increased capillary content, and collagen remodeling. Hypothesis: Here we test the novel hypothesis that GPX1 is an essential regulator of skeletal muscle adaptation during endurance exercise training. Methods: Male wildtype (WT) C57BL/6J mice and GPX1 knockout (GPX1-/-) mice (male, 4-month-old) were housed with horizontal running wheels that were locked (sedentary) or unlocked (wheel running, WR) for 28 days. After the final bout of exercise, gastrocnemius muscles were collected and evaluated for weight, fiber cross-sectional area (CSA), and capillarization. Results: No differences in running distance were detected between groups. Whereas WR increased gastrocnemius mass in WT, no change was detected in GPX1-/- mice (GPX1 x WR interaction, P=0.0497). Despite these beneficial changes, no interaction effects were noted between WT and GPX1-/- for fiber CSA or capillary measures. A significant main effect for fiber CSA was detected between WT and GPX1-/- mice under sedentary conditions, suggesting the requirement of GPX1 to maintain baseline fiber size. Conclusion: These findings demonstrate that GPX1 is an essential regulator of skeletal muscle mass in response to exercise training, yet this observation cannot be explained by changes in fiber size or capillarization. Further analyses, including fiber type-specific CSA assessment, is required to provide insight regarding these results. Funding: University of Illinois Summer Undergraduate Research Fellowship (to FH) and NASA Cooperative Agreement with Baylor College of Medicine (NNX16A069A; T0701; to MDB). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.