Small Molecules Dorsomorphin and LDN-193189 Inhibit Myostatin/GDF8 Signaling and Promote Functional Myoblast Differentiation*
| Autor: | Horbelt, D, Boergermann, JH, Chaikuad, A, Alfano, I, Williams, E, Lukonin, I, Timmel, T, Bullock, AN, Knaus, P |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Binding Sites
Activin Receptors Type II Molecular Sequence Data Myogenesis Cell Differentiation Smad2 Protein Myostatin Spodoptera musculoskeletal system Serine/Threonine Protein Kinase Myoblasts Bone Morphogenetic Protein (BMP) Mice Pyrimidines Sf9 Cells Small Molecule Animals Humans Pyrazoles Amino Acid Sequence Smad3 Protein Function and Dysfunction of the Nervous System Signal Transduction Protein Binding Transcription Factors |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | Background: GDF8/myostatin suppresses myogenic differentiation. Results: The small molecule inhibitors dorsomorphin and LDN-193189 bind to and inhibit the GDF8 receptor ActRII and ALK4. Conclusion: Dorsomorphin and LDN-193189 promote myogenesis in vitro. Significance: Detailed molecular characterization of small molecule inhibitors targeting the GDF8/myostatin pathway demonstrates their potential and risk when applied to promote muscle development. GDF8, or myostatin, is a member of the TGF-β superfamily of secreted polypeptide growth factors. GDF8 is a potent negative regulator of myogenesis both in vivo and in vitro. We found that GDF8 signaling was inhibited by the small molecule ATP competitive inhibitors dorsomorphin and LDN-193189. These compounds were previously shown to be potent inhibitors of BMP signaling by binding to the BMP type I receptors ALK1/2/3/6. We present the crystal structure of the type II receptor ActRIIA with dorsomorphin and demonstrate that dorsomorphin or LDN-193189 target GDF8 induced Smad2/3 signaling and repression of myogenic transcription factors. As a result, both inhibitors rescued myogenesis in myoblasts treated with GDF8. As revealed by quantitative live cell microscopy, treatment with dorsomorphin or LDN-193189 promoted the contractile activity of myotubular networks in vitro. We therefore suggest these inhibitors as suitable tools to promote functional myogenesis. |
| Databáze: | OpenAIRE |
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