Abstract
SummaryWnt-mediated signals are involved in many important steps in mammalian regeneration. In multiple cell types, the R-spondin (Rspo) family of secreted proteins potently activates the canonical Wnt/β-catenin pathway. Here, we identify Rspo1 as a mediator of skeletal muscle tissue repair. First, we show that deletion of Rspo1 results in global alteration of muscle regeneration kinetics following acute injury. We find that muscle progenitor cells lacking Rspo1 show delayed differentiation due to reduced activation of Wnt/β-catenin target genes. Furthermore, muscle cells lacking Rspo1 have a fusion phenotype leading to larger myotubes containing supernumerary nuclei both in vitro and in vivo. The increase in muscle fusion was dependent on downregulation of Wnt/β-catenin and upregulation of non-canonical Wnt7a/Fzd7/Rac1 signaling. We conclude that reciprocal control of antagonistic Wnt signaling pathways by Rspo1 in muscle stem cell progeny is a key step ensuring normal tissue architecture restoration following acute damage.
Highlights
Adult muscle stem cells, called satellite cells (MuSCs), located around the differentiated myofibers exist in a quiescent state and are readily identified through the expression of the pairedbox transcription factor Pax7 (Seale et al, 2000)
To determine if improved muscle cell fusion resulted in functional changes, we compared the contractile properties of regenerated muscle in situ using an index of fatigue resistance (Figure 2P) and specific maximal force, a marker of force production capacity (Figure 2Q). These experiments indicate that regenerated Rspo1-null muscles, while composed of larger myofibers containing more myonuclei, are functional, because we found no reductions in the performed assays
Our results indicate that Rspo1 negatively regulates muscle cell fusion and that its absence leads to the generation of larger myotubes containing more nuclei
Summary
Florian Bentzinger, ..., Marie-Christine Chaboissier, Anne-Amandine Chassot, Fabien Le Grand. Using mice lacking the Wnt enhancer Rspo, Lacour et al demonstrate that Rspo controls muscle cell fusion during skeletal muscle regeneration. Rspo1-null muscle progenitor cells differentiate less efficiently but fuse extensively compared to wild-type cells. Rspo is shown to regulate the antagonism between canonical and non-canonical Wnt signaling pathways.
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