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MUSCLE CELL BIOLOGY AND CELL MOTILITY

Regulation of myostatin expression and myoblast differentiation by FoxO and SMAD transcription factors

¹Department of Integrative Physiology, University of Colorado, Boulder, Colorado; and Departments of ²Medicine and ³Physiology and Biophysics, University of Illinois at Chicago College of Medicine, and ⁴Jesse Brown Department of Veterans Affairs Medical Center, Chicago, Illinois

Submitted 25 October 2005 ; accepted in final form 14 July 2006

Myostatin, a member of the transforming growth factor (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 were greater in fast- vs. slow-twitch 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 overexpression of SMAD2, -3, or -4 also resulted in a significant increase in myostatin promoter activity. Treatment with TGF- along with overexpression of SMAD2 and FoxO1 resulted in the largest increase in myostatin promoter activity. Finally, TGF- treatment and SMAD2 overexpression greatly potentiated FoxO1-mediated suppression of myoblast differentiation. 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.

skeletal muscle; atrophy; FKHR; forkhead; gene expression; promoter; C₂C₁₂ myotubes

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