Dual Roles of Adipose Tissue in Skeletal Muscle Regeneration: Pro-Regenerative Versus Maladaptive.

Abstract

Skeletal muscle accounts for approximately 40% of total body mass and is essential for locomotion, metabolic regulation and systemic homeostasis. Adipose tissue is increasingly recognized as an active component of the muscle's regenerative microenvironment. During muscle repair, adipose tissue contributes to local metabolic support and paracrine signalling, but its effects are highly context dependent. Tightly regulated presence of adipose tissue accompanies effective regeneration, whereas excessive or dysregulated ectopic fat accumulation leads to persistent functional impairment. This review synthesizes recent experimental and translational studies investigating the cellular origins, regulatory mechanisms and functional consequences of adipose tissue during skeletal muscle repair. We propose three potential therapeutic directions to improve pathological muscle repair by modulation of the adipose-related intramuscular regenerative microenvironment: (1) targeted modulation of fibro-adipogenic progenitors (FAPs) to curb pathological adipogenesis and fibrosis while leveraging beneficial mediators such as adiponectin and leptin; (2) adipose-derived stem cell transplantation and exosome-based approaches to deliver multipotent cells and remodel the repair microenvironment; and (3) induction of adipose browning to enhance energy availability, immune tone and vascularization while recognizing its context-dependent liabilities. Together, these strategies position adipose tissue as a plastic and environment-sensitive regulator of muscle regeneration and provide a framework for precision interventions to improve structural and functional outcomes.