Proliferation and fusion of myoblasts is a well-orchestrated process occurring during muscle development and regeneration. Although myoblasts are known to originate from muscle satellite cells, the molecular mechanisms that coordinate their commitment toward differentiation are poorly understood. Here, we present a novel role for the transcription factor Forkhead box protein C2 (Foxc2) in regulating proliferation and preventing premature differentiation of activated muscle satellite cells. We demonstrate that Foxc2 expression is upregulated early in activated mouse muscle satellite cells and then diminishes during myogenesis. In undifferentiated C2C12 myoblasts, downregulation of endogenous Foxc2 expression leads to a decrease in proliferation, whereas forced expression of FOXC2 sustains proliferation and prevents differentiation into myotubes. We also show that FOXC2 induces Wnt signaling by direct interaction with the Wnt4 (wingless-type MMTV integration site family member-4) promoter region. The resulting elevated expression of bone morphogenetic protein-4 (Bmp4) and RhoA-GTP proteins inhibits the proper myoblast alignment and fusion required for myotube formation. Interestingly, continuous forced expression of FOXC2 alters the commitment of C2C12 myoblasts toward osteogenic differentiation, which is consistent with FOXC2 expression observed in patients with myositis ossificans, an abnormal bone growth within muscle tissue. In summary, our results suggest that ( Muscle satellite cells are resident stem cells localized between the basal lamina and the sarcolemma of myofibers. During postnatal development, these satellite cells provide myonuclei for growth of skeletal muscle. In adult skeletal muscles, satellite cells comprise 1-4% of myofibers and remain quiescent 1,2 unless involved in homeostasis, hypertrophy or muscle repair at which time they become activated, proliferate and produce the myoblasts needed to replace or repair myofibers.2,3 Deregulation of factors involved in the maintenance of muscle homeostasis and in the differentiation of muscle precursors can lead to a variety of pathologic conditions, including muscular dystrophies and myositis ossificans or heterotopic ossification. 4,5 The role of muscle satellite cells in the pathology of these disorders is not well understood. Identification of key regulators and elucidation of the processes involved in satellite cell activation and differentiation could provide important insights into the etiology, treatment and/or prevention of muscle disorders.Recent studies have shown that bone morphogenetic proteins (BMPs) are important in the activation and proliferation of muscle satellite cells, and in the prevention of premature myogenic differentiation. 6,7 BMPs are members of the transforming growth factor-b (TGF-b) family that initiate signaling by binding to transmembrane type-1 and type-2 BMP receptors (BMPRs). Upon ligand binding, transphosphorylation of type-1 by type-2 receptors activates the receptor-regulated Smad (Sma and Mad-related protein) tr...
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