Age-Dependent Alterations in Glutathione Metabolites Following Muscle Injury

Age-related impairments in antioxidant defences contribute to delayed tissue repair and increased susceptibility to oxidative stress following muscle injury. Glutathione (GSH), a key cellular antioxidant, plays a central role in redox homeostasis and recovery processes. GSH is synthesized through a sequential process involving glutamic acid and cysteine, catalyzed by the rate-limiting enzyme glutamate cysteine ligase (GCL) to form γ-glutamyl cysteine (γGC), which subsequently combines with glycine to produce GSH. Using metabolomic profiling and acute skeletal muscle injury in mice, this study characterized age-dependent alterations in GSH biosynthesis. Clustering analysis identified that muscle from 12-month-old mice have a delayed GSH synthesis profile in response to injury compared to 3-month-old mice, with an age-dependent delay in γGC accumulation. This suggests that aging negatively influences metabolite profiles within the GSH synthesis pathway. As γGC lies downstream of this enzymatic step, its supplementation may bypass the GCL bottleneck. To test this, C2C12 myoblasts were treated with γGC (from 1-100 µg/mL), however this did not affect myoblast proliferation or differentiation. These data suggest detrimental age-related dysregulation of GSH-related metabolites in skeletal muscle repair, particularly γGC, however further examination of the role of exogenous γGC supplementation in this process is required to identify further therapeutic benefit.