TGFβ signalling acts as a molecular brake of myoblast fusion

Fusion of nascent myoblasts to pre-existing myofibres is critical for skeletal muscle growth and repair. The vast majority of molecules known to regulate myoblast fusion are necessary in this process. Here, we uncover, through high-throughput in vitro assays and in vivo studies in the chicken embryo, that TGF beta (SMAD2/3-dependent) signalling acts specifically and uniquely as a molecular brake on muscle fusion. While constitutive activation of the pathway arrests fusion, its inhibition leads to a striking over-fusion phenotype. This dynamic control of TGF beta signalling in the embryonic muscle relies on a receptor complementation mechanism, prompted by the merging of myoblasts with myofibres, each carrying one component of the heterodimer receptor complex. The competence of myofibres to fuse is likely restored through endocytic degradation of activated receptors. Altogether, this study shows that muscle fusion relies on TGF beta signalling to regulate its pace. Fusion of myoblasts is essential for muscle development and repair, but the molecular mechanism underlying this process remains unclear. Here, the authors show, using chicken embryos as a model, that TGF beta signalling inhibits fusion via a receptor complementation mechanism, and indicate the involvement of endocytic degradation of activated receptors in modulation of this process.

Automated summary

Fusion of myoblasts is essential for muscle development and repair, with TGF-beta signaling regulating the pace of fusion through a receptor complementation mechanism and endocytic degradation of activated receptors.