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Research Article

Wnt7a treatment ameliorates muscular dystrophy

Julia von Maltzahn, Jean-Marc Renaud, Gianni Parise, and Michael A. Rudnicki
PNAS first published November 26, 2012; https://doi.org/10.1073/pnas.1215765109
Julia von Maltzahn
aSprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6;
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Jean-Marc Renaud
bDepartment of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8M5; and
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Gianni Parise
cDepartment of Kinesiology, McMaster University, Hamilton, ON, Canada L8S 4K1
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Michael A. Rudnicki
aSprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6;
bDepartment of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8M5; and
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  • For correspondence: mrudnicki@ohri.ca
  1. Edited* by Kevin P. Campbell, University of Iowa Carver College of Medicine, Iowa City, IA, and approved October 31, 2012 (received for review September 11, 2012)

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Abstract

Duchenne muscular dystrophy (DMD) is a devastating genetic muscular disorder of childhood marked by progressive debilitating muscle weakness and wasting, and ultimately death in the second or third decade of life. Wnt7a signaling through its receptor Fzd7 accelerates and augments regeneration by stimulating satellite stem cell expansion through the planar cell polarity pathway, as well as myofiber hypertrophy through the AKT/mammalian target of rapamycin (mTOR) anabolic pathway. We investigated the therapeutic potential of the secreted factor Wnt7a for focal treatment of dystrophic DMD muscles using the mdx mouse model, and found that Wnt7a treatment efficiently induced satellite cell expansion and myofiber hypertrophy in treated mucles in mdx mice. Importantly, Wnt7a treatment resulted in a significant increase in muscle strength, as determined by generation of specific force. Furthermore, Wnt7a reduced the level of contractile damage, likely by inducing a shift in fiber type toward slow-twitch. Finally, we found that Wnt7a similarly induced myotube hypertrophy and a shift in fiber type toward slow-twitch in human primary myotubes. Taken together, our findings suggest that Wnt7a is a promising candidate for development as an ameliorative treatment for DMD.

  • noncanonical Wnt signaling
  • skeletal muscle

Footnotes

  • ↵1To whom correspondence should be addressed. E-mail: mrudnicki{at}ohri.ca.
  • Author contributions: J.v.M. and M.A.R. designed research; J.v.M. performed research; J.-M.R. and G.P. contributed new reagents/analytic tools; J.v.M. and M.A.R. analyzed data; and J.v.M. and M.A.R. wrote the paper.

  • Conflict of interest statement: M.A.R. is a founding scientist with Fate Therapeutics, who is developing Wnt7a as a therapeutic agent.

  • ↵*This Direct Submission article had a prearranged editor.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1215765109/-/DCSupplemental.

Freely available online through the PNAS open access option.

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Wnt7a treatment ameliorates muscular dystrophy
Julia von Maltzahn, Jean-Marc Renaud, Gianni Parise, Michael A. Rudnicki
Proceedings of the National Academy of Sciences Nov 2012, 201215765; DOI: 10.1073/pnas.1215765109

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Wnt7a treatment ameliorates muscular dystrophy
Julia von Maltzahn, Jean-Marc Renaud, Gianni Parise, Michael A. Rudnicki
Proceedings of the National Academy of Sciences Nov 2012, 201215765; DOI: 10.1073/pnas.1215765109
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