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Cited by 501Muscle Physiology and DisordersTGF-β signaling in diseasesGenetics and Physical Performance

Regulation of muscle growth by multiple ligands signaling through activin type II receptors

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Lee, Se-Jin, Reed, Lori A., Davies, Monique V., Girgenrath, Stefan, Goad, Mary E. P., Tomkinson, Kathy N., Wright, Jill F., Barker, Christopher +12 more·2005·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0505996102PMC PMC1306793
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Abstract

Myostatin is a secreted protein that normally functions as a negative regulator of muscle growth. Agents capable of blocking the myostatin signaling pathway could have important applications for treating human muscle degenerative diseases as well as for enhancing livestock production. Here we describe a potent myostatin inhibitor, a soluble form of the activin type IIB receptor (ACVR2B), which can cause dramatic increases in muscle mass (up to 60% in 2 weeks) when injected into wild-type mice. Furthermore, we show that the effect of the soluble receptor is attenuated but not eliminated in Mstn -/- mice, suggesting that at least one other ligand in addition to myostatin normally functions to limit muscle growth. Finally, we provide genetic evidence that these ligands signal through both activin type II receptors, ACVR2 and ACVR2B, to regulate muscle growth in vivo .

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Crossref · 10.1073/pnas.0505996102

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  • The function of MSTN in muscle is at least partially redundant with that of activin A.

    “The function of MSTN in muscle is at least partially redundant with that of another TGF-β family member, activin A (13–16).”

    From Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight (2020) · cites this paper as [13]

    The Results and Discussion show that a ligand other than myostatin also suppresses muscle growth, and that the soluble receptor blocks activin activity in a cell assay. But the paper says the muscle-regulating ligand’s identity is unknown; it does not establish that activin A has a redundant function with myostatin in muscle. Page numbers are unavailable in our copy. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • ACVR2B/Fc decoy receptor is a potent inhibitor of MSTN and activin A signaling and can induce significant muscle growth when given systemically to wild type mice.

    “A decoy receptor (ACVR2B/Fc) consisting of the extracellular, ligand-binding domain of ACVR2B fused to an immunoglobulin Fc domain has been shown to be a potent inhibitor of MSTN and activin A signaling and, as a result, can induce significant muscle growth when given systemically to wild type mice (13).”

    From Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight (2020) · cites this paper as [13]

    The Results and Discussion report that ACVR2B/Fc blocked myostatin and activin activity in cell culture, and that systemic injections significantly increased muscle growth in wild-type mice. The paper calls the tested ligand “activin,” not specifically activin A, and does not establish that blocking activin caused the growth observed in mice; it identifies the additional growth-suppressing ligand only as an unidentified possibility. Page numbers were not provided in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • ACVR2B/Fc increased lean body mass in ground mice by 11% in just 12 d.

    “We showed previously that treatment with ACVR2B/Fc can induce rapid muscle growth (13), and indeed, the decoy receptor increased lean body mass in ground mice by 11% in just 12 d (Fig. 1D).”

    From Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight (2020) · cites this paper as [13]

  • Knockout of ACVR2A causes muscle hypertrophy in female mice.

    “Another study reveals that knockout of ACVR2A causes muscle hypertrophy in female mice (55).”

    From Sex-Based Differences in Skeletal Muscle Kinetics and Fiber-Type Composition (2015) · cites this paper as [55]

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Authors
Lee, S.-J., Reed, L. A., Davies, M. V., Girgenrath, S., Goad, M. E. P., Tomkinson, K. N., Wright, J. F., Barker, C., Ehrmantraut, G., Holmstrom, J., Trowell, B., Gertz, B., Jiang, M.-S., Sebald, S. M., Matzuk, M., Li, E., Liang, L.-F., Quattlebaum, E., Stotish, R. L., & Wolfman, N. M.
Affiliations
Johns Hopkins University (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2005-12-05
Volume
102
Issue
50
Pages
18117-18122
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0505996102
PMC
PMC1306793
OpenAlex
W2047284298
Cited by
501
References
30
Citations by year
2026: 12 · 2025: 8 · 2024: 13 · 2023: 11 · 2022: 22 · 2021: 20 · 2020: 27 · 2019: 23 · 2018: 13 · 2017: 21 · 2016: 34 · 2015: 31 · 2014: 31 · 2013: 35 · 2012: 35
FWCI
6.78
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (R01CA088866, R01 CA 88866)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD35887, R01-HD32067, R01HD035887, R01HD032067)
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 › Genetics › Genetics and Physical Performance
Keywords
myostatin, activin type II receptor, ACVR2B, ACVR2, muscle growth, myostatin inhibitors, soluble receptor, muscle mass, Mstn knockout mice, animal husbandry
MeSH terms
Animals, Ligands, Organ Size, Signal Transduction, Transforming Growth Factor beta, Mice, Knockout, Muscle, Skeletal, Activin Receptors, Type II, Mice, Myostatin

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