N-Acetylcysteine Prevents Skeletal Muscle Cisplatin-Induced Atrophy by Inducing Myogenic microRNAs and Maintaining the Redox Balance

Cisplatin (CIS) is a widely used chemotherapeutic agent known for its efficacy; however, it induces several adverse effects, most notably cachexia, which is characterized by progressive loss of skeletal muscle mass, weakness, and reduced body weight. N-acetylcysteine (NAC) a compound with antioxidants properties, has been shown to mitigate CIS-induced neurotoxicity in experimental models. This study aimed to investigate the myoprotective effects of NAC during CIS treatment and explore the redox and molecular mechanisms involved in this response. For this, female Wistar rats were divided into four experimental groups: Control, NAC (300 mg/day/8 days), CIS (3 mg/kg i.p for 5 days), and NAC + CIS (NAC for 8 days, with CIS administered from day 4 onward). After treatment, muscle strength, redox status, mitochondrial biogenesis, expression of myogenic microRNAs and morphological changes were evaluated. CIS treatment caused muscle atrophy, decreased GSH/GSSG ratio, impaired cellular function, increased lipid peroxidation and altered antioxidant enzymes activity. These effects were mitigated by NAC coadministration. CIS also reduced the mtDNA/nDNA ratio; however, NAC treatment tended to increase TFAM and PGC-1α expression levels. Furthermore, CIS suppressed the expression of muscular miR-1-3p, miR-133a-3p and miR-206-3p, while NAC restored their levels when co-administered with CIS. These findings suggest that NAC may serve as a promising adjuvant therapeutic strategy to counteract CIS-induced myotoxicity through redox regulation and modulation of molecular pathways related to muscle integrity and regeneration.