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J. Biol. Chem., Vol. 283, Issue 11, 7027-7035, March 14, 2008

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Identification of a Novel Pool of Extracellular Pro-myostatin in Skeletal Muscle^*

Sarah B. Anderson, Alfred L. Goldberg, and Malcolm Whitman¹

From the Department of Developmental Biology, Harvard School of Dental Medicine, and the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115

Myostatin, a transforming growth factor-β superfamily ligand, negatively regulates skeletal muscle growth. Generation of the mature signaling peptide requires cleavage of pro-myostatin by a proprotein convertase, which is thought to occur constitutively in the Golgi apparatus. In serum, mature myostatin is found in an inactive, non-covalent complex with its prodomain. We find that in skeletal muscle, unlike serum, myostatin is present extracellularly as uncleaved pro-myostatin. In cultured cells, co-expression of pro-myostatin and latent transforming growth factor-β-binding protein-3 (LTBP-3) sequesters pro-myostatin in the extracellular matrix, and secreted pro-myostatin can be cleaved extracellularly by the proprotein convertase furin. Co-expression of LTBP-3 with myostatin reduces phosphorylation of Smad2, and ectopic expression of LTBP-3 in mature mouse skeletal muscle increases fiber area, consistent with reduction of myostatin activity. We propose that extracellular pro-myostatin constitutes the major pool of latent myostatin in muscle. Post-secretion activation of this pool by furin family proprotein convertases may therefore represent a major control point for activation of myostatin in skeletal muscle.

Received for publication, August 13, 2007 , and in revised form, December 28, 2007.

^* This work was supported by Muscular Dystrophy Association Grant 4217, National Institutes of Health Grant HD-29468 (to M. W.), and grants from the Ellison Foundation and the Muscular Dystrophy Association (to A. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 188 Longwood Ave., Boston, MA 02115. Tel.: 617-432-1320; E-mail: mwhitman{at}hms.harvard.edu.

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