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Follistatin complexes Myostatin and antagonises Myostatin-mediated inhibition of myogenesis
Open accessAbstract
Follistatin is known to antagonise the function of several members of the TGF-beta family of secreted signalling factors, including Myostatin, the most powerful inhibitor of muscle growth characterised to date. In this study, we compare the expression of Myostatin and Follistatin during chick development and show that they are expressed in the vicinity or in overlapping domains to suggest possible interaction during muscle development. We performed yeast and mammalian two-hybrid studies and show that Myostatin and Follistatin interact directly. We further show that single modules of the Follistatin protein cannot associate with Myostatin suggesting that the entire protein is required for the interaction. We analysed the interaction kinetics of the two proteins and found that Follistatin binds Myostatin with a high affinity of 5.84 x 10(-10) M. We next tested whether Follistatin suppresses Myostatin activity during muscle development. We confirmed our previous observation that treatment of chick limb buds with Myostatin results in a severe decrease in the expression of two key myogenic regulatory genes Pax-3 and MyoD. However, in the presence of Follistatin, the Myostatin-mediated inhibition of Pax-3 and MyoD expression is blocked. We additionally show that Myostatin inhibits terminal differentiation of muscle cells in high-density cell cultures of limb mesenchyme (micromass) and that Follistatin rescues muscle differentiation in a concentration-dependent manner. In summary, our data suggest that Follistatin antagonises Myostatin by direct protein interaction, which prevents Myostatin from executing its inhibitory effect on muscle development.
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“Follistatin might enhance SkM hypertrophy due to its ability to bind and neutralize myostatin [184,199], increasing the mass of SkM available for glucose and FFA uptake and oxidation.”
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Metadata
- Authors
- Amthor, H., Nicholas, G., McKinnell, I., Kemp, C. F., Sharma, M., Kambadur, R., & Patel, K.
- Affiliations
- Royal Veterinary College (GB)
- AgResearch (NZ)
- University of Reading (GB)
- Corresponding author
- Patel, Ketan
- Venue
- Developmental Biology
- Publisher
- Elsevier BV
- Published
- 2004-06
- Volume
- 270
- Issue
- 1
- Pages
- 19-30
- ISSN
- 0012-1606 (ISSN-L)
- OpenAlex
- W2068756636
- Cited by
- 401
- References
- 39
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 15 · 2023: 10 · 2022: 19 · 2021: 17 · 2020: 21 · 2019: 16 · 2018: 26 · 2017: 18 · 2016: 32 · 2015: 22 · 2014: 25 · 2013: 20 · 2012: 16
- FWCI
- 5.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Biology (publishedVersion)
- PubMed (publishedVersion)
- CentAUR (University of Reading) (acceptedVersion)
- Carleton University's Institutional Repository (MacOdrum Library, Carleton University) (submittedVersion, other-oa)
- RVC Research Online (Royal Veterinary College) (submittedVersion, cc-by)
- Funders
- Wellcome Trust
- Deutsche Forschungsgemeinschaft
- 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 › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- follistatin, myostatin, TGF-beta superfamily, protein-protein interaction, myogenesis, chick limb bud, Pax3, MyoD, micromass culture, limb mesenchyme, binding affinity
- MeSH terms
- PAX3 Transcription Factor, Animals, Cell Differentiation, Chick Embryo, DNA-Binding Proteins, Embryonic Structures, Extremities, Cricetinae, Membrane Glycoproteins, Recombinant Fusion Proteins, Transcription Factors, Transforming Growth Factor beta, CHO Cells, MyoD Protein, Mice, Knockout, Surface Plasmon Resonance, Two-Hybrid System Techniques, Muscle Development, Follistatin, Culture Techniques, Mice, Paired Box Transcription Factors, Myostatin
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