Wnt7a–Fzd7 signalling directly activates the Akt/mTOR anabolic growth pathway in skeletal muscle

Wnt signalling regulates development and differentiation through both canonical and non-canonical pathways. Rudnicki and colleagues find that Wnt7a–Fzd7 activates Gαs to promote Akt/mTOR pathway activation, and show that this non-canonical Wnt signalling pathway elicits myofibre hypertrophy in vivo. Wnt7a signals through its receptor Fzd7 to activate the planar-cell-polarity pathway and drive the symmetric expansion of satellite stem cells resulting in enhanced repair of skeletal muscle. In differentiated myofibres, we observed that Wnt7a binding to Fzd7 directly activates the Akt/mTOR growth pathway, thereby inducing myofibre hypertrophy. Notably, the Fzd7 receptor complex was associated with Gαs and PI(3)K and these components were required for Wnt7a to activate the Akt/mTOR growth pathway in myotubes. Wnt7a–Fzd7 activation of this pathway was completely independent of IGF-receptor activation. Together, these experiments demonstrate that Wnt7a–Fzd7 activates distinct pathways at different developmental stages during myogenic lineage progression, and identify a non-canonical anabolic signalling pathway for Wnt7a and its receptor Fzd7 in skeletal muscle.