Neonatal Mcam⁺ mural cells are bipotent progenitors for skeletal myogenesis and fibrogenesis

Skeletal muscle regeneration is predominantly driven by satellite cells, yet the contributions of other resident progenitor populations remain unclear. Using Mcam-CreER; R26-tdTomato mice, we combined lineage tracing with RNA sequencing and cell transplantation assays to evaluate Mcam + mural cell fates and myogenic potential. Mcam⁺ mural cells exhibit distinct fates across postnatal development and injury contexts. During the postnatal period, these cells function as myogenic progenitors and contribute to dystrophin⁺ myofibers. In adulthood, they maintain a stable vascular identity under homeostasis. However, adult Mcam⁺ mural cells transdifferentiate into PDGFRα⁺ fibroblasts and incorporate into the fibrotic stroma following cardiotoxin-induced skeletal muscle injury. Notably, RNA sequencing demonstrates that neonatal Mcam⁺ mural cells exhibit a transcriptional program enriched for myogenic and mesenchymal signatures. When transplanted into injured muscle, these mural cells engrafted and differentiated into myofibers. Collectively, our results identify Mcam⁺ mural cells as a bipotent progenitor population exhibiting distinct fates during muscle growth and repair, underscoring their therapeutic potential in muscle regeneration.