Abstract
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-beta-catenin (Act-beta-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-beta-Cat. Finally, we provide evidence that the Act-beta-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.
Highlights
Adult mammalian skeletal muscle displays a tremendous capacity for regeneration, a point exemplified by examining the histological characteristics of muscle following acute chemical insult when large areas of damaged tissue are totally restored to normal architecture within 10 days
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
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
Summary
Adult mammalian skeletal muscle displays a tremendous capacity for regeneration, a point exemplified by examining the histological characteristics of muscle following acute chemical insult when large areas of damaged tissue are totally restored to normal architecture within 10 days. The nuclei within a syncytially organised myofibre exist in a postmitotic state, rendering them incapable of providing cellular material for repairing damaged tissue or postnatal growth. Termed satellite cells because of their peripheral location relative to the muscle fibres, these cells are normally found in a quiescent state. During periods of muscle regeneration and growth, satellite cells become activated, proliferate and fuse either with one another or with existing muscle fibres. Proliferating satellite cells can exit the cell cycle to replenish the stem cell niche in anticipation of future rounds of regeneration
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