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1 Integrative Physiology, University of Colorado, Boulder, Boulder, Colorado, United States
2 Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois, United States; Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois, United States; Jesse Brown VA Medical Center, Chicago, Illinois, United States
* To whom correspondence should be addressed. E-mail: allendl{at}colorado.edu.
Myostatin, a member of the TGF-
family, plays an important role in regulating skeletal muscle growth and differentiation. Here we examined the role of FoxO1 and SMAD transcription factors in regulating myostatin gene expression and myoblast differentiation in C2C12 myotubes in vitro. Both myostatin and FoxO1 mRNA expression was greater in fast vs. slow skeletal muscles in vivo. Moreover, expression of a constitutively active form of FoxO1 increased myostatin mRNA and increased activity of a myostatin promoter reporter construct in differentiated C2C12 myotubes. Mutagenesis of highly conserved FoxO or SMAD binding sites significantly decreased myostatin promoter activity, and binding assays showed that both FoxO1 and SMADs bind to their respective sites in the myostatin promoter. Treatment with TGF- and/or over-expression of SMADs 2, 3, or 4 also resulted in a significant increase in myostatin promoter activity. Treatment with TGF- along with over-expression of SMAD2 and FoxO1 resulted in the largest increase in myostatin promoter activity. Finally, TGF- treatment and SMAD2 over-expression greatly potentiated the FoxO1-mediated suppression of myoblast differentiation in vitro. Together these data demonstrate that FoxO1 and SMAD transcription factors regulate the expression of myostatin and contribute to the control of muscle cell growth and differentiation.
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