The role of sestrin2 in skeletal muscle regeneration after injury

Despite advances in the understanding of muscle degeneration, the mechanisms governing muscle regeneration under stress conditions remain poorly defined. Sestrin2 (Sesn2) is a stress-inducible gene that plays a crucial role in metabolic balance, nutrient sensing, and redox homeostasis, while protecting against muscle atrophy through multiple pathways. However, its precise role in skeletal muscle differentiation and regeneration, particularly under injury conditions, remains incompletely understood. In this study, we investigated the role of Sesn2 in skeletal muscle homeostasis and regeneration using <i>in vitro</i> and <i>in vivo</i> models, complemented by transcriptome analyses. Sesn2 knockdown in C2C12 myoblasts induced senescence-like morphological changes, accompanied by upregulation of nicotinamide adenine dinucleotide phosphate oxidase 4 and transforming growth factor-beta, leading to impaired myogenic differentiation. Intriguingly, Sesn2-knockout mice developed normally under basal conditions but exhibited regenerative defects, characterized by prolonged inflammation, necrosis, and delayed muscle regeneration, following cardiotoxininduced injury. Transcriptomic analysis of Sesn2 transgenic mice further supported this conditional role, revealing that genes involved in mitochondrial function and myogenesis were preferentially upregulated under immobilized conditions compared to basal conditions. These findings underscore that the context-dependent role of Sesn2 is essential for effective muscle regeneration under injury, positioning it as a potential therapeutic target for degenerative muscle diseases.