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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 (TGFβ) pathway is active in adult muscle cells throughout fusion. We find TGFβ signaling reduces cell fusion, regardless of the cells’ ability to move and establish cell-cell contacts. In contrast, inhibition of TGFβ signaling enhances cell fusion and promotes branching between myotubes in mouse and human. Exogenous addition of TGFβ protein in vivo during muscle regeneration results in a loss of muscle function while inhibition of TGFβR2 induces the formation of giant myofibers. Transcriptome analyses and functional assays reveal that TGFβ controls the expression of actin-related genes to reduce cell spreading. TGFβ 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 (TGFβ) signaling.

The myotendinous junction transfers forces from muscle to tendon. As such, it must hold two tissues of completely different biological and cellular compositions as well as mechanical properties (kPa-MPa to MPa-GPa) and is subject to frequent stresses of high amplitude. This region remains a weak point of the muscle-tendon unit and is involved in frequent injuries. We here produce fibrin (40 mg/mL, E0 =0.10 ± 0.02 MPa) and collagen (60 mg/mL, E0=0.57 ± 0.05 MPa) threads as well as mixed collagen:fibrin threads (3:2 in mass, E0 = 0.33 ± 0.05 MPa) and investigate the difference of affinity between primary murine myoblasts and tenoblasts. We demonstrate a similar behavior of cells on mixed and fibrin threads with high adherence of tenoblasts and myoblasts, in comparison to collagen threads that promote high adherence and proliferation of tenoblasts but not of myoblasts. Besides, we show that myoblasts on threads differentiate but do not fuse, on the contrary to 2D control substrates, raising the question of the effect of substrate curvature on the ability of myoblasts to fusein vitro.