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First published online 12 August 2008
doi: 10.1242/jcs.026534

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Canonical Wnt signalling induces satellite-cell proliferation during adult skeletal muscle regeneration

¹ School of Biological Sciences, AMS Building, University of Reading, Whiteknights, PO Box 228, Reading, Berkshire RG6 6AJ, UK
² Institute of Anatomy, Ludwigs-Maximilians-University of Munich, Pettenkoferstr. 11, 80336 Munich, Germany
³ Department of Veterinary Basic Sciences, Royal Veterinary College, London NW1 0TU, UK
⁴ Dubowitz Neuromuscular Unit, Imperial College, South Kensington Campus, London SW7 2AZ, UK
⁵ Brighton and Sussex Medical School, Falmer Campus, Brighton BN1 9PX, UK

^* Author for correspondence (e-mail: ketan.patel{at}reading.ac.uk)

Accepted 9 June 2008

Satellite cells represent the stem cell population of adult skeletal muscle. The molecular mechanisms that control the proliferation of satellite cells are not well understood. In this study, we show that in response to injury, myofibres activate Wnt ligand transcription and activate a reporter cell line that is sensitive to the canonical Wnt-signalling pathway. Activated satellite cells on isolated cultured myofibres show robust expression of activated-β-catenin (Act-β-Cat), a key downstream transcriptional coactivator of canonical Wnt signalling. We provide evidence that the Wnt family of secreted glycoproteins act on satellite cells in a ligand-specific manner. Overexpression of Wnt1, Wnt3a or Wnt5a protein causes a dramatic increase in satellite-cell proliferation. By contrast, exposure of satellite cells to Wnt4 or Wnt6 diminishes this process. Moreover, we show that the prolonged satellite-cell quiescence induced by inhibitory Wnt is reversible and exposing inhibited satellite cells to stimulatory Wnt signalling restores their proliferation rate. Stimulatory Wnt proteins induce premature satellite cell BrdU incorporation as well as nuclear translocation of Act-β-Cat. Finally, we provide evidence that the Act-β-Cat translocation observed in single fibres during in vitro culture also occurs in cases of acute and chronic skeletal muscle regeneration in rodents and humans. We propose that Wnt proteins may be key factors that regulate the rate of satellite-cell proliferation on adult muscle fibres during the wound-healing response.

Key words: Satellite cell, Wnt signalling, β-catenin, Skeletal muscle, Regeneration

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