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Originally published In Press as doi:10.1074/jbc.M206379200 on August 22, 2002

J. Biol. Chem., Vol. 277, Issue 43, 40735-40741, October 25, 2002
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The Myostatin Propeptide and the Follistatin-related Gene Are Inhibitory Binding Proteins of Myostatin in Normal Serum*

Jennifer J. HillDagger §, Monique V. Davies, Adele A. Pearson, Jack H. WangDagger , Rodney M. HewickDagger , Neil M. Wolfman, and Yongchang QiuDagger

From the Departments of Dagger  Protein Chemistry and Proteomics and  Musculoskeletal Science, Wyeth Research, Cambridge, Massachusetts 02140

Myostatin, also known as growth and differentiation factor 8, is a member of the transforming growth factor beta  superfamily that negatively regulates skeletal muscle mass (1). Recent experiments have shown that myostatin activity is detected in serum by a reporter gene assay only after activation by acid, suggesting that native myostatin circulates as a latent complex (2). We have used a monoclonal myostatin antibody, JA16, to isolate the native myostatin complex from normal mouse and human serum. Analysis by mass spectrometry and Western blot shows that circulating myostatin is bound to at least two major proteins, the myostatin propeptide and the follistatin-related gene (FLRG). The myostatin propeptide is known to bind and inhibit myostatin in vitro (3). Here we show that this interaction is relevant in vivo, with a majority (>70%) of myostatin in serum bound to its propeptide. Studies with recombinant V5-His-tagged FLRG protein confirm a direct interaction between mature myostatin and FLRG. Functional studies show that FLRG inhibits myostatin activity in a reporter gene assay. These experiments suggest that the myostatin propeptide and FLRG are major negative regulators of myostatin in vivo.

* 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.

§ To whom correspondence should be addressed: Wyeth Research, 87 Cambridge Park Dr., Cambridge, MA 02140. E-mail: jhill@wyeth.com.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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