Activation of latent myostatin by the BMP-1/tolloid family of metalloproteinases

Wolfman, Neil M.; McPherron, Alexandra C.; Pappano, William N.; Davies, Monique V.; Song, Kening; Tomkinson, Kathleen N.; Wright, Jill F.; Zhao, Liz; Sebald, Suzanne M.; Greenspan, Daniel S.; Lee, Se-Jin

doi:10.1073/pnas.2534946100

Cited by 454Muscle Physiology and DisordersTGF-β signaling in diseasesProtease and Inhibitor Mechanisms

Activation of latent myostatin by the BMP-1/tolloid family of metalloproteinases

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Wolfman, Neil M., McPherron, Alexandra C., Pappano, William N., Davies, Monique V., Song, Kening, Tomkinson, Kathleen N., Wright, Jill F., Zhao, Liz +3 more·2003·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.2534946100PMC PMC307655

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Abstract

Myostatin is a transforming growth factor β 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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BMP-1 would be predicted to increase activation of latent MSTN by proteolytic cleavage of the MSTN propeptide.
“which would be predicted to increase activation of latent MSTN by proteolytic cleavage of the MSTN propeptide (53).”
From Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight (2020) · cites this paper as [53]

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Walker, R. G., Kato, T., Ben Driss, L., Williams, S. A., Hinterberg, M. A., Janjic, N., Gelinas, A. D., Carpenter, M. A., Kattamuri, C., Walter, J. E., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-61815-w · Cited by 4 · see citing works

Authors: Wolfman, N. M., McPherron, A. C., Pappano, W. N., Davies, M. V., Song, K., Tomkinson, K. N., Wright, J. F., Zhao, L., Sebald, S. M., Greenspan, D. S., & Lee, S.-J.
Affiliations: University of Wisconsin System (US)
University of Wisconsin–Madison (US)
ORCID: McPherron, Alexandra C.
Pappano, William N.
Greenspan, Daniel S.
Lee, Se-Jin
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2003-12-11
Volume: 100
Issue: 26
Pages: 15842-15846
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.2534946100
PMC: PMC307655
OpenAlex: W2166947475
Cited by: 454
References: 27
Citations by year: 2026: 11 · 2025: 15 · 2024: 10 · 2023: 13 · 2022: 18 · 2021: 13 · 2020: 20 · 2019: 13 · 2018: 23 · 2017: 15 · 2016: 27 · 2015: 26 · 2014: 21 · 2013: 22 · 2012: 25
FWCI: 6.17
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: American Heart Association
National Institutes of Health
National Cancer Institute (R01CA088866, T32CA009139)
National Institute of General Medical Sciences (R01GM063471)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR047746)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD035887)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Keywords: myostatin, myostatin propeptide, propeptide cleavage, skeletal muscle growth, muscle mass, protease inhibitors
MeSH terms: Animals, Female, Cricetinae, Luciferases, Metalloendopeptidases, Mice, Inbred BALB C, Protein Precursors, Proteins, Recombinant Fusion Proteins, Transforming Growth Factor beta, CHO Cells, Genes, Reporter, Muscle, Skeletal, Bone Morphogenetic Proteins, Metalloproteases, Mice, Tolloid-Like Metalloproteinases, Bone Morphogenetic Protein 1, Myostatin

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Activation of latent myostatin by the BMP-1/tolloid family of metalloproteinases

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