Effects of lifelong systemic NOX2 loss or GPX1 overexpression on skeletal muscle aging

Age-related muscle loss, or sarcopenia, contributes significantly to morbidity and mortality. Due to its primarily post-mitotic and metabolically dynamic nature, skeletal muscle is especially sensitive to oxidative damage. Therefore, the elevated production of reactive oxygen species (ROS) and the reduced antioxidant capacities associated with biological aging likely play a role in the development of sarcopenia. NADPH oxidase 2 (NOX2) comprises the single greatest source of ROS (i.e., superoxide) during contraction and its activity has been shown to increase with aging in muscle. On the other hand, Glutathione Peroxidase 1 (GPX1) characterizes a potent antioxidant enzyme responsible for the breakdown of harmful peroxides, and its expression decreases in aging muscle. However, whether changes in NOX2 or GPX1 could independently contribute to age-related muscle dysfunction is not currently known. To this end, we sought to characterize skeletal muscle aging in two lifelong, systemic models: NOX2 knockout (KO) and GPX1 overexpression (OE). In each model, we studied four groups of male C57BL6 mice. For example, the NOX2 study included young (3-4 months) and old (19-24 months) WT and KO groups. Effects of genotype in young animals were either subtle or non-existent across both models and all measurements. Nevertheless, compared to old WT, NOX2 KO animals did not gain bodyweight and had ~20% lower muscle mass (p=0.0001 and 0.0011). On the other hand, chronic GPX1 OE did not affect bodyweight or muscle mass in old animals. Lifelong NOX2 KO did not affect muscle fatigability, yet it led to a ~25% reduction in maximal torque and ~20% slower relaxation (during fatigued and non-fatigued conditions) (p=0.0001, 0.031). Interestingly, lifelong GPX1 OE also did not alter any of these functional indices in old animals. Taken together, these studies highlight: a) a beneficial role of NOX2 in muscle size and contractile function during aging, and b) an insufficient role of GPX1 in improving muscle function during aging. Thus, the role of these enzymes during muscle aging is likely more nuanced than initially hypothesized. 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.