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

Nature Cell Biology volume 14, pages 186–191 (2012)Cite this article

Abstract

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.

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Figure 1: Wnt7a induces hypertrophy in differentiated myotubes and myofibres.
Figure 2: Wnt7a induces muscle hypertrophy through its receptor Fzd7.
Figure 3: Wnt7a activates the Akt/mTOR pathway in differentiated myotubes and myofibres.
Figure 4: Wnt7a induces hypertrophy independent of IGFR activity.
Figure 5: The Fzd7 receptor complex contains PI(3)K and the G protein Gαs.

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Acknowledgements

The authors thank F. Price and V. Soleimani for critical reading of the manuscript. M.A.R. holds the Canada Research Chair in Molecular Genetics and is an International Research Scholar of the Howard Hughes Medical Institute. C.F.B. is supported by the Swiss National Science Foundation. This work was financially supported by grants from the Muscular Dystrophy Association, Canadian Institutes of Health Research, National Institutes of Health, Howard Hughes Medical Institute and the Canada Research Chair Program.

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Authors and Affiliations

  1. Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada

    Julia von Maltzahn, C. Florian Bentzinger & Michael A. Rudnicki

  2. Department of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada

    Michael A. Rudnicki

  3. Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada

    Michael A. Rudnicki

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  1. Julia von Maltzahn
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  2. C. Florian Bentzinger
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  3. Michael A. Rudnicki
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J.v.M. and M.A.R. planned the experimental design, analysed data and wrote the paper. J.v.M. and C.F.B. conducted the experiments.

Corresponding author

Correspondence to Michael A. Rudnicki.

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Competing interests

M.A.R. is a founding scientist and consultant with Fate Therapeutics.

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von Maltzahn, J., Bentzinger, C. & Rudnicki, M. Wnt7a–Fzd7 signalling directly activates the Akt/mTOR anabolic growth pathway in skeletal muscle. Nat Cell Biol 14, 186–191 (2012). https://doi.org/10.1038/ncb2404

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