Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 286, Issue 12, Pages 10649-10659Publisher
ELSEVIER
DOI: 10.1074/jbc.M110.169391
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Funding
- National Institutes of Health [P20 RR015555, R01 AR055278, P20 RR018789]
- Maine Medical Center Research Institute [P20 RR018789]
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R-spondins (RSPOs) are a recently characterized family of secreted proteins that activate WNT/beta-catenin signaling. In this study, we investigated the potential roles of the RSPO proteins during myogenic differentiation. Overexpression of the Rspo1 gene or administration of recombinant RSPO2 protein enhanced mRNA and protein expression of a basic helix-loop-helix (bHLH) class myogenic determination factor, MYF5, in both C2C12 myoblasts and primary satellite cells, whereas MYOD or PAX7 expression was not affected. RSPOs also promoted myogenic differentiation and induced hypertrophic myotube formation in C2C12 cells. In addition, Rspo2 and Rspo3 gene knockdown by RNA interference significantly compromised MYF5 expression, myogenic differentiation, and myotube formation. Furthermore, Myf5 expression was reduced in the developing limbs of mouse embryos lacking the Rspo2 gene. Finally, we demonstrated that blocking of WNT/beta-catenin signaling by DKK1 or a dominant-negative form of TCF4 reversed MYF5 expression, myogenic differentiation, and hypertrophic myotube formation induced by RSPO2, indicating that RSPO2 exerts its activity through the WNT/beta-catenin signaling pathway. Our results provide strong evidence that RSPOs are key positive regulators of skeletal myogenesis acting through the WNT/beta-catenin signaling pathway.
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