Abstract/Summary

Orchestration of numerous molecular pathways is required to deliver stem cells mediated tissue regeneration. As such, mechanisms controlling one aspect of regeneration are often antagonistic to others. Much attention has focused on Wntmediated signalings as this family is involved in many important steps in mammalian regeneration. In many cell types, the R-spondin (Rspo) family of secreted proteins acts as potent activators of the canonical Wnt/β-catenin pathway. Here, we identify Rspo1 as a mediator of skeletal muscle tissue repair. First, we show that Rspo1-null muscles do not display any abnormalities at the basal level. However deletion of Rspo1 results in global alteration of muscle regeneration kinetics following acute injury. We found that muscle progenitor cells lacking Rspo1 show delayed differentiation. Transcriptome analysis demonstrated that Rspo1 is required for the activation of Wnt/β-catenin target genes in muscle cells. Furthermore, muscle cells lacking Rspo1 have a fusion phenotype leading to larger myotubes containing supernumerary nuclei both in vitro and in vivo. We found the increase in muscle fusion was dependent on downregulation of Wnt/β-catenin and up-regulation of non-canonical Wnt7a/Fzd7/Rac1 signaling. We conclude that reciprocal control of canonical and non-canonical Wnt signaling pathways by Rspo1 in muscle stem cell progeny is a key step ensuring normal tissue architecture restoration following acute damage.