Abstract
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 TGFβ (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 TGFβ 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 TGFβ signalling to regulate its pace.
Highlights
Fusion of nascent myoblasts to pre-existing myofibres is critical for skeletal muscle growth and repair
Myoblast fusion occurs after muscle specification and early differentiation, themselves regulated by the myogenic regulatory factors (MRFs) MYF5, MYOD and MYOG1–3
Validating the approach, we observed that molecules previously known to be necessary for myoblast fusion in vertebrates and invertebrates were identified through the screen (Supplementary Table 3)
Summary
Fusion of nascent myoblasts to pre-existing myofibres is critical for skeletal muscle growth and repair. While constitutive activation of the pathway arrests fusion, its inhibition leads to a striking over-fusion phenotype. This dynamic control of TGFβ 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. A recent analysis of myoblast fusion during chicken embryonic development showed that the various myogenic populations that co-exist in the muscle masses display an unexpected variety of fusion behaviours, suggesting that additional mechanisms must exert temporal and spatial control on the fusion machinery, modulating whether progenitors that are competent to fuse do so and at what pace[9]. The competence to fuse is likely restored through endocytic degradation of the activated receptor
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