Enhancers integrate microenvironmental signals in muscle stem cells during regeneration in health, disease, and aging

Effective skeletal muscle regeneration requires muscle stem cells (MuSCs) to continuously interpret and respond to signals from their surrounding microenvironment. These niche-derived cues, including inflammatory, extracellular matrix, paracrine, metabolic, and biomechanical signals, direct MuSC progression through quiescence, activation, proliferation, and differentiation by reshaping gene expression programs. Increasing evidence suggests that transcriptional enhancers serve as a key regulatory interface through which environmental information is translated into transcriptional output. Enhancer activity is governed by the coordinated action of lineage-defining transcription factors, histone modifiers, chromatin remodelers, transcriptional coactivators, and architectural proteins that together regulate chromatin accessibility, enhancer-promoter communication, and gene activation. Recent work has shown that enhancer landscapes and three-dimensional genome organization are highly dynamic during muscle regeneration and become altered in aging and disease. In this review, we examine how enhancer-associated mechanisms enable MuSCs to interpret niche-derived signals, highlighting the roles of transcription factor networks, chromatin remodeling complexes, and enhancer-promoter interactions in coordinating gene expression. We further discuss how disruption of enhancer regulation contributes to impaired regeneration in aging and muscular dystrophy, where altered chromatin states and genome organization lead to aberrant transcriptional responses. Understanding how these regulatory elements integrate complex environmental signals will be essential for defining the mechanisms underlying muscle regeneration and may provide new avenues for therapeutic intervention.