Regulation of Myostatin Expression and Myoblast Differentiation by FoxO and SMAD

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Am J Physiol Cell Physiol. 2006 Aug 2

Regulation of Myostatin Expression and Myoblast Differentiation by

FoxO and SMAD Transcription Factors.

DL, Unterman TG.

Integrative Physiology, University of Colorado, Boulder, Boulder,

Colorado, United States.

Myostatin, a member of the TGF-beta 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-beta and/or over-expression of SMADs 2, 3, or 4

also resulted in a significant increase in myostatin promoter

activity. Treatment with TGF-beta along with over-expression of SMAD2

and FoxO1 resulted in the largest increase in myostatin promoter

activity.

Finally, TGF-beta 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.