RESUMEN
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 (TGFß) pathway is active in adult muscle cells throughout fusion. We find TGFß signaling reduces cell fusion, regardless of the cells' ability to move and establish cell-cell contacts. In contrast, inhibition of TGFß signaling enhances cell fusion and promotes branching between myotubes in mouse and human. Exogenous addition of TGFß protein in vivo during muscle regeneration results in a loss of muscle function while inhibition of TGFßR2 induces the formation of giant myofibers. Transcriptome analyses and functional assays reveal that TGFß controls the expression of actin-related genes to reduce cell spreading. TGFß signaling is therefore requisite to limit mammalian myoblast fusion, determining myonuclei numbers and myofiber size.