Activation of Latent Myostatin by the BMP-1/tolloid Family of Metalloproteinases

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2003 Dec 13

PMID 14671324

Citations 183

Authors

Neil M Wolfman

Alexandra C McPherron

William N Pappano

Monique V Davies

Kening Song

Kathleen N Tomkinson

Jill F Wright

Liz Zhao

Suzanne M Sebald

Daniel S Greenspan

Se-Jin Lee

Affiliations

Soon will be listed here.

Abstract

Myostatin is a transforming growth factor beta family member that acts as a negative regulator of skeletal muscle growth. Myostatin circulates in the blood of adult mice in a noncovalently held complex with other proteins, including its propeptide, which maintain the C-terminal dimer in a latent, inactive state. This latent form of myostatin can be activated in vitro by treatment with acid; however, the mechanisms by which latent myostatin is activated in vivo are unknown. Here, we show that members of the bone morphogenetic protein-1/tolloid (BMP-1/TLD) family of metalloproteinases can cleave the myostatin propeptide in this complex and can thereby activate latent myostatin. Furthermore, we show that a mutant form of the propeptide resistant to cleavage by BMP-1/TLD proteinases can cause significant increases in muscle mass when injected into adult mice. These findings raise the possibility that members of the BMP-1/TLD family may be involved in activating latent myostatin in vivo and that molecules capable of inhibiting these proteinases may be effective agents for increasing muscle mass for both human therapeutic and agricultural applications.

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References

Scott I, Imamura Y, Pappano W, Troedel J, Recklies A, Roughley P . Bone morphogenetic protein-1 processes probiglycan. J Biol Chem. 2000; 275(39):30504-11. DOI: 10.1074/jbc.M004846200. View

Hill J, Davies M, Pearson A, Wang J, Hewick R, Wolfman N . The myostatin propeptide and the follistatin-related gene are inhibitory binding proteins of myostatin in normal serum. J Biol Chem. 2002; 277(43):40735-41. DOI: 10.1074/jbc.M206379200. View

Maeda S, Dean D, Gay I, Schwartz Z, Boyan B . Activation of latent transforming growth factor beta1 by stromelysin 1 in extracts of growth plate chondrocyte-derived matrix vesicles. J Bone Miner Res. 2001; 16(7):1281-90. DOI: 10.1359/jbmr.2001.16.7.1281. View

Wagner K, McPherron A, Winik N, Lee S . Loss of myostatin attenuates severity of muscular dystrophy in mdx mice. Ann Neurol. 2002; 52(6):832-6. DOI: 10.1002/ana.10385. View

Bogdanovich S, Krag T, Barton E, Morris L, Whittemore L, Ahima R . Functional improvement of dystrophic muscle by myostatin blockade. Nature. 2002; 420(6914):418-21. DOI: 10.1038/nature01154. View

Whittemore L, Song K, Li X, Aghajanian J, Davies M, Girgenrath S . Inhibition of myostatin in adult mice increases skeletal muscle mass and strength. Biochem Biophys Res Commun. 2003; 300(4):965-71. DOI: 10.1016/s0006-291x(02)02953-4. View

Hill J, Qiu Y, Hewick R, Wolfman N . Regulation of myostatin in vivo by growth and differentiation factor-associated serum protein-1: a novel protein with protease inhibitor and follistatin domains. Mol Endocrinol. 2003; 17(6):1144-54. DOI: 10.1210/me.2002-0366. View

Pappano W, Steiglitz B, Scott I, Keene D, Greenspan D . Use of Bmp1/Tll1 doubly homozygous null mice and proteomics to identify and validate in vivo substrates of bone morphogenetic protein 1/tolloid-like metalloproteinases. Mol Cell Biol. 2003; 23(13):4428-38. PMC: 164836. DOI: 10.1128/MCB.23.13.4428-4438.2003. View

Lyons R, Keski-Oja J, Moses H . Proteolytic activation of latent transforming growth factor-beta from fibroblast-conditioned medium. J Cell Biol. 1988; 106(5):1659-65. PMC: 2115066. DOI: 10.1083/jcb.106.5.1659. View

10.

Sato Y, Rifkin D . Inhibition of endothelial cell movement by pericytes and smooth muscle cells: activation of a latent transforming growth factor-beta 1-like molecule by plasmin during co-culture. J Cell Biol. 1989; 109(1):309-15. PMC: 2115489. DOI: 10.1083/jcb.109.1.309. View

11.

Lee S, Kessler E, Greenspan D . Analysis of site-directed mutations in human pro-alpha 2(I) collagen which block cleavage by the C-proteinase. J Biol Chem. 1990; 265(35):21992-6. View

12.

McPherron A, Lawler A, Lee S . Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature. 1997; 387(6628):83-90. DOI: 10.1038/387083a0. View

13.

Grobet L, Martin L, Poncelet D, Pirottin D, Brouwers B, Riquet J . A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle. Nat Genet. 1997; 17(1):71-4. DOI: 10.1038/ng0997-71. View

14.

Kambadur R, Sharma M, Smith T, Bass J . Mutations in myostatin (GDF8) in double-muscled Belgian Blue and Piedmontese cattle. Genome Res. 1997; 7(9):910-6. DOI: 10.1101/gr.7.9.910. View

15.

McPherron A, Lee S . Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci U S A. 1997; 94(23):12457-61. PMC: 24998. DOI: 10.1073/pnas.94.23.12457. View

16.

Piccolo S, Agius E, Lu B, Goodman S, Dale L, De Robertis E . Cleavage of Chordin by Xolloid metalloprotease suggests a role for proteolytic processing in the regulation of Spemann organizer activity. Cell. 1997; 91(3):407-16. PMC: 3070600. DOI: 10.1016/s0092-8674(00)80424-9. View

17.

Marques G, Musacchio M, Shimell M, Cho K, OConnor M . Production of a DPP activity gradient in the early Drosophila embryo through the opposing actions of the SOG and TLD proteins. Cell. 1997; 91(3):417-26. DOI: 10.1016/s0092-8674(00)80425-0. View

18.

Blader P, Rastegar S, Fischer N, Strahle U . Cleavage of the BMP-4 antagonist chordin by zebrafish tolloid. Science. 1998; 278(5345):1937-40. DOI: 10.1126/science.278.5345.1937. View

19.

Grobet L, Poncelet D, Royo L, Brouwers B, Pirottin D, Michaux C . Molecular definition of an allelic series of mutations disrupting the myostatin function and causing double-muscling in cattle. Mamm Genome. 1998; 9(3):210-3. DOI: 10.1007/s003359900727. View

20.

Scott I, Blitz I, Pappano W, Imamura Y, Clark T, Steiglitz B . Mammalian BMP-1/Tolloid-related metalloproteinases, including novel family member mammalian Tolloid-like 2, have differential enzymatic activities and distributions of expression relevant to patterning and skeletogenesis. Dev Biol. 1999; 213(2):283-300. DOI: 10.1006/dbio.1999.9383. View