Evidence of a redox-dependent regulation of satellite cell activity and regeneration in human skeletal muscle following aseptic injury: a randomized controlled trial.

Satellite cells are essential for skeletal muscle regeneration, with their activity tightly regulated by glutathione (GSH) metabolism and redox balance. Effective regeneration requires an optimal redox hormetic range and balanced GSH levels, as both oxidative and reductive distress can impair redox signaling, satellite cell differentiation, and muscle repair. Despite its significance, redox-regulated regeneration responses in human skeletal muscle remain underexplored. Twenty-four recreationally active males provided a resting muscle biopsy and were stratified to a low or high GSH group based on their muscle glutathione levels. Participants completed two experimental trials of N-acetylcysteine (NAC) and placebo supplementation using a randomized, double-blind, crossover, repeated-measures design. NAC or placebo was administered during a 7-day loading phase before, immediately after, and daily for 8 days following an eccentric exercise injury protocol of the quadriceps muscle. Muscle biopsies, blood samples, muscle function, and soreness assessments were obtained at baseline, post-loading, and 2 and 8 days post-injury to assess cellular, morphological and functional parameters during recovery from injury. We demonstrate that restoration of intramuscular GSH balance in GSHlow individuals through NAC supplementation enhances satellite cell activity and myogenic response, promoting muscle regeneration and functional recovery. In contrast, in GSHhigh individuals, NAC supplementation propagated an aberrant Nrf2 response, resulting in compromised satellite cell kinetics and delayed skeletal muscle repair. These findings underscore the essentiality of GSH and redox balance in promoting effective muscle healing, highlighting the need for personalized antioxidant therapies that optimize skeletal muscle regeneration and recovery in humans.