Macrophage Subpopulation Promotes Skeletal Muscle Regeneration Through <scp>HGF</scp>/<scp>MET</scp> Signaling‐Mediated Skeletal Muscle Stem Cell Proliferation

Macrophages are key regulators of skeletal muscle regeneration, yet the specific macrophage subpopulations responsible for this process and their cell-cell interactions remain insufficiently understood, as does the mechanism underlying age-related impairment of skeletal muscle regeneration. We utilized single-cell RNA sequencing to identify transcriptionally distinct macrophage subpopulations within skeletal muscle from young (8-week-old) and aged (24-month-old) mice. Among them, the Mac_1 subpopulation interacted with muscle satellite cells (MuSCs) and promoted their proliferation through HGF/c-Met signaling that suppressed Cdkn1b expression. This interaction was critical for efficient muscle regeneration in vivo and in a 3D-muscle organoid model. The age-related decline in muscle regeneration was associated with reduced HGF expression in Mac_1 macrophages. Administration of exogenous HGF to aged mice and macrophage-depleted young mice partially rescued the impaired muscle regeneration. This study elucidates a mechanism of skeletal muscle regeneration that offers insight into potential strategies for preventing and treating skeletal muscle diseases, including sarcopenia.