Defining the role of APC and canonical WNT signaling in embryonic and adult myogenesis

The Wnt/β-catenin signaling pathway, also called canonical Wnt signaling, is implicated in a large variety of biological processes, including embryonic axis determination, organogenesis and adult stem cells homeostasis. Canonical Wnt signaling regulates the stability of β-catenin, a transcriptional co-activator that, in absence of Wnt ligands, is targeted to proteasomal degradation by a multiproteic complex comprising the Adenomatous Polyposis Coli (APC) tumor suppressor. Activation of canonical Wnt signaling blocks β-catenin degradation and results in its accumulation into the nucleus, where it induces the expression of Wnt target genes. During embryonic myogenesis, the process of skeletal muscle formation, a proportion of pluripotent dermomyotomal cells restrict their fate to acquire a myogenic identity and differentiate into contractile myofibers, the functional units of skeletal muscle. Myogenesis can take place also in adult skeletal muscle. Indeed, upon acute injury or in pathological conditions, quiescent muscle-specific stem cells, called satellite cells, become activated and give rise to myogenic progenitors that massively proliferate, differentiate and fuse to form new myofibers and restore tissue functionality. In addition, a proportion of proliferating progenitors returns back to quiescence and replenish the pool of satellite cells in order to maintain the regenerative potential of skeletal muscle. The role of canonical Wnt signaling in the cell fate choice that drives multipotent dermomyotomal cells toward the myogenic lineage remains elusive. Similarly, a possible involvement of the Wnt/β-catenin cascade has been hypothesized in satellite cells during adult skeletal muscle regeneration, but different approaches came to contradictory results. In this study, we use genetic mouse models to investigate the precise role of canonical Wnt signaling in embryonic and adult myogenesis. In vivo constitutive overactivation of Wnt/β-catenin signaling following conditional deletion of APC, the major intracellular negative regulator of the pathway, results in complete abrogation of skeletal muscle formation and regeneration. By combining ex vivo and in vitro approaches, we show that canonical Wnt signaling hyperactivation alters cell cycle progression and results in programmed cell death. Conversely, conditional inactivation of β-catenin does not perturb the proliferative ability of myogenic progenitors but rather affects their differentiation. Collectively, our results demonstrate at least two distinct roles of the Wnt/β-catenin cascade in skeletal muscle. First, during myogenic initiation, canonical Wnt signaling must be inhibited to allow proper activation of myogenesis, in particular to elicit myogenic commitment of dermomyotomal cells and activation of adult satellite cells. Second, in myogenic progression, the Wnt/β-catenin pathway is required in both embryonic and adult muscle progenitors for proper differentiation and myofibers formation.