Exercise-induced metabolites: messengers linking epigenetic enzymes and cell remodeling in skeletal muscle regeneration

Skeletal muscle regeneration is a highly coordinated process that depends on muscle satellite cells (MuSCs) and is intricately regulated by metabolic and epigenetic mechanisms. Exercise, recognized as a vital non-pharmaceutical intervention, can significantly enhance the regenerative capacity of skeletal muscle; however, the underlying molecular mechanisms remain inadequately understood. Recent studies suggest that the metabolic products generated during exercise are not merely by-products of energy metabolism; rather, they act as essential regulatory factors involved in epigenetic reprogramming. These metabolites, which include lactate, α-ketoglutarate (α-KG), acetyl-CoA, nicotinamide adenine dinucleotide (NAD + ), and S-adenosylmethionine (SAM), serve as substrates, cofactors, or signaling molecules. They directly influence the activities of epigenetic enzymes such as histone acetyltransferases, deacetylases, demethylases, and DNA methyltransferases. This mechanism converts dynamic changes in metabolic states into stable chromatin modifications and gene expression programs, thereby affecting the activation, proliferation, and differentiation of MuSCs. This article presents a systematic review of the regulatory mechanisms that govern the metabolic-epigenetic axis during skeletal muscle regeneration. It emphasizes the role of exercise-induced metabolites in facilitating cell reprogramming through chromatin remodeling. Additionally, the article proposes an integrated theoretical framework that underscores the dynamic coordination of metabolic signals and their time-dependent characteristics throughout various stages of regeneration. Furthermore, it explores potential clinical translational strategies aimed at targeting metabolic-epigenetic coupling, including personalized exercise interventions and metabolic supplementation regimens. A comprehensive understanding of this regulatory network is expected to provide a new theoretical foundation for the precise treatment of muscle injuries, age-related sarcopenia, and metabolic diseases.