N-acetyl cysteine and skeletal muscle health across aging and disease models: A systematic review of preclinical and preliminary human evidence

Background: Age- and disease-related muscle deterioration is driven by oxidative stress, chronic inflammation, mitochondrial dysfunction, and impaired regeneration. N-acetylcysteine (NAC), a glutathione precursor, may modulate these pathways, but evidence is mainly preclinical. Methods: This systematic review followed PRISMA 2020 guidelines. PubMed, Scopus, Embase, Web of Science, and the Cochrane Library were searched (January 2000–January 2024) for in vivo or human studies evaluating NAC, alone or combined, on muscle-related outcomes. Eligible studies reported muscle mass, morphology, function, or biomarkers of oxidative, inflammatory, or apoptotic stress. Risk of bias was assessed using SYRCLE, RoB 2.0, or the Newcastle–Ottawa Scale. Results and discussion: Eight studies were included (seven in vivo, one with human data). Animal models received NAC dosages ranging from 500 mg/kg (i.p.) to 1–2% in drinking water, while the human trial utilized 1800 mg/day for 7 days. NAC significantly improved maximum force generation at 7 and 14 days post-injury, preserved tetanic force, and reduced oxidative stress markers (e.g., lipid peroxidation) and inflammatory cytokines like IL-1β and IL-6. Human data were limited to acute fatigue recovery. Evidence was limited by heterogeneity in dosing and study design. Human data were scarce and restricted to acute fatigue recovery. Conclusion: NAC shows potential in modulating mechanisms of muscle deterioration, but evidence remains largely preclinical. Well-designed randomized trials in older adults, particularly with sarcopenia or frailty, are needed.