Myostatin Inhibits Myoblast Differentiation by Down-regulating MyoD Expression*

By Brett C. Langley, Mark Thomas, A. Bishop, Mridula Sharma, S. Gilmour, R. Kambadur. Journal of Biological Chemistry, 2002

949 citations recorded by the source corpus.

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-negativeSmad3 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.

Subfields: Genetics, Molecular Biology, Rheumatology

View Paper: https://www.semanticscholar.org/paper/231f3f8c9ccb0dbbfc58e7804e5b4aa9458b4793

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In Genetics

1. J. Hawley
2. Vernon G. Coffey

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1. J. Hawley
2. Vernon G. Coffey

Citations in the corpus

• Exercise is the real polypill. (2013, background): “Myostatin, the first described secreted muscle factor to fulfil the criteria of a myokine, is a potent muscle-growth inhibitor (302) that acts via SMAD signaling (398) or mammalian target-of-rapamycin (mTOR) inhibition (12, 249, 271, 301, 403, 426, 476).”
• Enhancement of meat production by environmental manipulations in embryo and young broilers (2006, background): “…cell proliferation and differentiation (Thomas et al., 2000; Joulia et al., 2003) by World’s Poultry Science Journal, Vol. 62, September 2006 489 maintaining them in their quiescent state (McCroskery et al., 2003) and by downregulating the expression of MyoD family members (Langley et al., 2002).”
• The Molecular Bases of Training Adaptation (2007, background): “MAFBx is a mediator of atrophy involved in the breakdown of muscle protein while Myostatin negatively regulates hypertrophy processes (Langley et al. 2002; Hoffman and Nader 2004).”
• Important metabolic pathways in poultry embryos prior to hatch (2008, background): “As in mammals, insulin-like growth factors I and II (IGF-I and IGF-II) in poultry stimulate growth, development, and intermediary metabolism (Taylor et al., 2001; 494 World's Poultry Science Journal, Vol. 64, December 2008 Langley et al., 2002; Joulia et al. 2003; Foye, 2005).”
• Myostatin negatively regulates satellite cell activation and self-renewal (2003, result): “Consistent with this hypothesis, Rios et al. (2002) and Langley et al. (2002) very recently demonstrated that excess Myostatin in DM blocks the differentiation of C2C12 myoblasts by inhibiting MyoD expression.”