Abstract
BackgroundThe 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.MethodsWe employed TCF-reporter mice and performed analysis of embryos and of muscle groups. We further isolated fetal myoblasts and performed cell and molecular analyses.ResultsWe 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.ConclusionsThese results demonstrate a novel interaction between canonical Wnt and BMP signaling that induces myogenic differentiation towards slow muscle phenotype.
Highlights
The Wnts are secreted proteins that play important roles in skeletal myogenesis, muscle fiber type diversification, neuromuscular junction formation and muscle stem cell function
Canonical Wnt signaling is activated during fetal myogenesis and reduced in adult muscle As the first step to investigate the function of Wnt signaling in myogenesis, we used the T-cell factor (TCF)-lacZ transgenic reporter mouse to examine the activity of the canonical Wnt signaling pathway in embryonic and adult muscles
Β-gal activity was undetectable in EDL and the adult fast (TA), muscles that are predominantly enriched with fast type myofibers, but was readily detected in part of the diaphragm (Figure 1G) and soleus (Figure 1H), muscles that are known to be enriched with slow myofibers
Summary
The Wnts are secreted proteins that play important roles in skeletal myogenesis, muscle fiber type diversification, neuromuscular junction formation and muscle stem cell function. Within the embryonic myogenic progenitors, Wnt regulate the expression of Pax3/7, MyoD and Myf, Wnt signaling is involved in the regulation of postnatal satellite cell function and skeletal muscle regeneration. Satellite cells are muscle resident stem cells responsible for postnatal regeneration of injured muscles. Wnt-5a and Wnt-7a induce muscle resident CD45+ stem cells to undergo myogenic specification and differentiation [13]. Wnt-7a acts through the non-canonical Wnt signaling pathway to stimulate the symmetric expansion of satellite cells and promote skeletal muscle hypertrophy [14,15]. Canonical Wnt activation was shown to induce satellite cell proliferation during skeletal muscle regeneration [16]. Contradictory results showing that activation of canonical Wnt signaling is necessary to counteract Notch signaling to induce myogenic differentiation were reported [17]. In the aged niche, elevated systemic Wnt molecules impede myogenic differentiation and facilitate satellite cell fate conversion to fibroblastic cell lineages [18]
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