TGFβ signaling curbs cell fusion and muscle regeneration

Francesco Girardi, Asiman Datye, Majid Ebrahimi, Dilani G. Gamage, Anissa Taleb, Lorenzo Giordani, Bruno Cadot, Douglas P. Millay, Penney M Gilbert, and Fabien Le Grand

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Received Date: 26th February 19

Fusion of muscle progenitor cells is necessary for skeletal muscle development and repair. Cell fusion is a multistep process involving cell migration, adhesion, membrane remodeling and actin-nucleation pathways to generate multinucleated myotubes. While the cellular and molecular mechanisms promoting muscle cell fusion have been intensely investigated in recent years, molecular brakes restraining cell–cell fusion events to control syncytia formation have remained elusive. Here, we show that transforming growth factor beta (TGFβ) signaling is active in adult muscle cells throughout the fusion process and reduce muscle cell fusion independently of the differentiation step. In contrast, inhibition of TGFβ signaling enhances cell fusion and promotes branching between myotubes, a mechanism we find is conserved across mice and human. Pharmacological modulation of the pathway in vivo perturbs muscle regeneration after injury. Exogenous addition of TGFβ protein results in a loss of muscle function while inhibition of the TGFβ pathway induces the formation of giant myofibres. Transcriptome analyses and functional assays revealed that TGFβ acts on actin dynamics to reduce cell spreading through modulation of actin-based protrusions. Together our results reveal a signaling pathway that limits mammalian myoblast fusion and add a new level of understanding to the molecular regulation of myogenesis.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

Nature Communications

Nature Research, Springer Nature