Journal Article β-Catenin Activation in Muscle Progenitor Cells Regulates Tissue Repair

Rudolf, Anja  ,  Schirwis, Elija  ,  Giordani, Lorenzo  ,  Parisi, Alice  ,  Lepper, Christoph  ,  Taketo, Makoto Mark  ,  Le Grand, Fabien

15 ( 8 )  , pp.1277 - 1290 , 2016-05-10 , Elsevier
Skeletal muscle regeneration relies on a pool of resident muscle stem cells called satellite cells (MuSCs). Following injury-induced destruction of the myofibers, quiescent MuSCs are activated and generate transient amplifying progenitors (myoblasts) that will fuse to form new myofibers. Here, we focus on the canonical Wnt signaling pathway and find that either conditional β-catenin disruption or activation in adult MuSCs results in perturbation of muscle regeneration. Using both in vivo and in vitro approaches, we observed that myoblasts lacking β-catenin show delayed differentiation, whereas myoblasts with constitutively active β-catenin undergo precocious growth arrest and differentiation. Transcriptome analysis further demonstrated that Wnt/β-catenin signaling interacts with multiple pathways and, more specifically, TGF-β signaling. Indeed, exogenous TGF-β2 stimulation restores the regenerative potential of muscles with targeted β-catenin disruption in MuSCs. We conclude that a precise level of β-catenin activity is essential for regulating the amplification and differentiation of MuSC descendants during adult myogenesis. Using muscle stem cell-specific β-catenin gain-of-function and loss-of-function mutations, Rudolf et al. demonstrate that muscle progenitor cells (MPCs) require the canonical Wnt/β-catenin pathway during skeletal muscle regeneration. In vivo and in vitro, MPCs differentiate less efficiently when β-catenin is absent, whereas conditional activation of β-catenin pushes MPCs toward precocious differentiation.

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