Resolvin E1 promotes the resolution of inflammation and enhances myogenic responses during aged skeletal muscle regeneration

Abstract Efficient muscle regeneration relies on the coordinated crosstalk between muscle stem cells (MuSCs) and their surrounding niche. Specialized pro-resolving mediators (SPMs), like resolvins, serve as critical autocrine and paracrine signals within this microenvironment, with macrophages acting as one of the primary sources of SPMs required to resolve inflammation and boost myogenesis. However, while dysregulation of endogenous SPM synthesis in aged skeletal muscle is known to drive chronic inflammation, the specific role of these lipid mediators during aged muscle regeneration remains poorly characterized. Here, we examine whether Resolvin E1 (RvE1) can accelerate the resolution of inflammation and improve the regenerative capacity of aged skeletal muscle. In vitro , RvE1 reduces pro-inflammatory gene expression and drives macrophages toward an anti-inflammatory phenotype. In aged mice, post-injury RvE1 treatment accelerates neutrophil clearance, expands the myogenic cell pool, and enhances myoblast differentiation, resulting in a trend toward improved muscle contractile function. Overall, our findings suggest that RvE1 is a therapeutic candidate that enhances aged muscle regeneration by concurrently resolving inflammation and driving myogenesis.