RT Journal Article
SR Electronic
T1 TGFβ signaling curbs cell fusion and muscle regeneration
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 557009
DO 10.1101/557009
A1 Francesco Girardi
A1 Anissa Taleb
A1 Lorenzo Giordani
A1 Bruno Cadot
A1 Asiman Datye
A1 Majid Ebrahimi
A1 Dilani G. Gamage
A1 Douglas P. Millay
A1 Penney M Gilbert
A1 Fabien Le Grand
YR 2019
UL http://biorxiv.org/content/early/2019/02/21/557009.abstract
AB 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. 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 and 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.