Wnt/β-catenin controls follistatin signalling to regulate satellite cell myogenic potential

Background: Adult skeletal muscle regeneration is a highly orchestrated process involving the activation and proliferation of satellite cells, an adult skeletal muscle stem cell. Activated satellite cells generate a transient amplifying progenitor pool of myoblasts that commit to differentiation and fuse into multinucleated myotubes. During regeneration, canonical Wnt signalling is activated and has been implicated in regulating myogenic lineage progression and terminal differentiation. Methods: Here, we have undertaken a gene expression analysis of committed satellite cell-derived myoblasts to examine their ability to respond to canonical Wnt/beta-catenin signalling. Results: We found that activation of canonical Wnt signalling induces follistatin expression in myoblasts and promotes myoblast fusion in a follistatin-dependent manner. In growth conditions, canonical Wnt/beta-catenin signalling prime myoblasts for myogenic differentiation by stimulating myogenin and follistatin expression. We further found that myogenin binds elements in the follistatin promoter and thus acts downstream of myogenin during differentiation. Finally, ectopic activation of canonical Wnt signalling in vivo promoted premature differentiation during muscle regeneration following acute injury. Conclusions: Together, these data reveal a novel mechanism by which myogenin mediates the canonical Wnt/beta-catenin-dependent activation of follistatin and induction of the myogenic differentiation process.