Abstract
Background
The Wnts are secreted proteins that play important roles in skeletal myogenesis, muscle fiber type diversification, neuromuscular junction formation and muscle stem cell function. How Wnt proteins orchestrate such diverse activities remains poorly understood. Canonical Wnt signaling stabilizes β-catenin, which subsequently translocate to the nucleus to activate the transcription of TCF/LEF family genes.
Methods
We employed TCF-reporter mice and performed analysis of embryos and of muscle groups. We further isolated fetal myoblasts and performed cell and molecular analyses.
Results
We found that canonical Wnt signaling is strongly activated during fetal myogenesis and weakly activated in adult muscles limited to the slow myofibers. Muscle-specific transgenic expression of a stabilized β-catenin protein led to increased oxidative myofibers and reduced muscle mass, suggesting that canonical Wnt signaling promotes slow fiber types and inhibits myogenesis. By TCF-luciferase reporter assay, we identified Wnt-1 and Wnt-3a as potent activators of canonical Wnt signaling in myogenic progenitors. Consistent with in vivo data, constitutive overexpression of Wnt-1 or Wnt-3a inhibited the proliferation of both C2C12 and primary myoblasts. Surprisingly, Wnt-1 and Wnt-3a overexpression up-regulated BMP-4, and inhibition of BMP-4 by shRNA or recombinant Noggin protein rescued the myogenic inhibitory effect of Wnt-1 and Wnt-3a. Importantly, Wnt-3a or BMP-4 recombinant proteins promoted slow myosin heavy chain expression during myogenic differentiation of fetal myoblasts.
Conclusions
These results demonstrate a novel interaction between canonical Wnt and BMP signaling that induces myogenic differentiation towards slow muscle phenotype.
Keywords
Skeletal muscle; Fetal myoblasts; Canonical Wnt signaling; BMP4 signaling; Differentiation; Slow muscle specification
Date of this Version
3-5-2013
DOI
10.1186/2044-5040-3-5
Recommended Citation
Kuroda, Kazuki; Kuang, Shihuan; Taketo, Makoto M.; and Rudnicki, Michael A., "Canonical Wnt Signaling Induces BMP-4 to Specify Slow Myofibrogenesis of Fetal Myoblasts" (2013). Department of Animal Sciences Faculty Publications. Paper 14.
http://dx.doi.org/10.1186/2044-5040-3-5
Comments
This is the publisher pdf of Kazuki Kuroda, Shihuan Kuang, Makoto M Taketo, Michael A Rudnicki. Canonical Wnt Signaling Induces BMP-4 to Specify Slow Myofibrogenesis of Fetal Myoblasts. Skeletal Muscle 2013, 3:5 (5 March 2013) and is available at: 10.1186/2044-5040-3-5.