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J. Biol. Chem., Vol. 277, Issue 51, 49831-49840, December 20, 2002
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From Myostatin, a negative regulator of myogenesis, is
shown to function by controlling the proliferation of myoblasts. In
this study we show that myostatin is an inhibitor of myoblast
differentiation and that this inhibition is mediated through Smad 3. In vitro, increasing concentrations of recombinant mature
myostatin reversibly blocked the myogenic differentiation of myoblasts,
cultured in low serum media. Western and Northern blot analysis
indicated that addition of myostatin to the low serum culture media
repressed the levels of MyoD, Myf5, myogenin, and p21 leading to the
inhibition of myogenic differentiation. The transient transfection of
C2C12 myoblasts with MyoD expressing constructs
did not rescue myostatin-inhibited myogenic differentiation. Myostatin
signaling specifically induced Smad 3 phosphorylation and increased
Smad 3·MyoD association, suggesting that Smad 3 may mediate the
myostatin signal by interfering with MyoD activity and expression.
Consistent with this, the expression of dominant-negative
Smad3 rescued the activity of a MyoD
promoter-reporter in C2C12 myoblasts treated
with myostatin. Taken together, these results suggest that myostatin
inhibits MyoD activity and expression via Smad 3 resulting in the
failure of the myoblasts to differentiate into myotubes. Thus we
propose that myostatin plays a critical role in myogenic
differentiation and that the muscular hyperplasia and hypertrophy seen
in animals that lack functional myostatin is because of deregulated
proliferation and differentiation of myoblasts.
Myostatin Inhibits Myoblast Differentiation by
Down-regulating MyoD Expression*
§,,§,,¶
Animal Genomics, AgResearch, Private Bag 3123, East Street, Hamilton, New Zealand and the § Faculty of
Medicine and Health Science, University of Auckland, Private Bag 92019, Auckland, New Zealand
*
This work was supported by the Marsden Fund of New Zealand
and the New Zealand Foundation for Research Science and Technology (FRST).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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