Abstract
Muscle cell fusion is critical for forming and maintaining multinucleated myotubes during skeletal muscle development and regeneration. However, the molecular mechanisms directing cell-cell fusion are not fully understood. Here, we identify platelet-derived growth factor receptor beta (PDGFRβ) signaling as a key modulator of myocyte fusion in adult muscle cells. Our findings demonstrate that genetic deletion of Pdgfrβ enhances muscle regeneration and increases myofiber size, whereas PDGFRβ activation impairs muscle repair. Inhibition of PDGFRβ activity promotes myonuclear accretion in both mouse and human myotubes, whereas PDGFRβ activation stalls myotube development by preventing cell spreading to limit fusion potential. Transcriptomics analysis show that PDGFRβ signaling cooperates with TGFβ signaling to direct myocyte size and fusion. Mechanistically, PDGFRβ signaling requires STAT1 activation, and blocking STAT1 phosphorylation enhances myofiber repair and size during regeneration. Collectively, PDGFRβ signaling acts as a regenerative checkpoint and represents a potential clinical target to rapidly boost skeletal muscle repair.