Tgf Beta Signaling Curbs Cell Fusion And Muscle Regeneration

Muscle cell fusion is a multistep process involving cell migration, adhesion, membrane remodeling and actin-nucleation pathways to generate multinucleated myotubes. However, molecular brakes restraining cell-cell fusion events have remained elusive. Here we show that transforming growth factor beta (TGF beta) pathway is active in adult muscle cells throughout fusion. We find TGF beta signaling reduces cell fusion, regardless of the cells' ability to move and establish cell-cell contacts. In contrast, inhibition of TGF beta signaling enhances cell fusion and promotes branching between myotubes in mouse and human. Exogenous addition of TGF beta protein in vivo during muscle regeneration results in a loss of muscle function while inhibition of TGF beta R2 induces the formation of giant myofibers. Transcriptome analyses and functional assays reveal that TGF beta controls the expression of actin-related genes to reduce cell spreading. TGF beta signaling is therefore requisite to limit mammalian myoblast fusion, determining myonuclei numbers and myofiber size. The fusion of muscle progenitor cells to form syncytial myofibers is required for skeletal muscle development and regeneration. Here, the authors describe a novel and specific molecular regulation of muscle cell fusion driven by transforming growth factor beta (TGF beta) signaling.