1. Small molecules dorsomorphin and LDN-193189 inhibit myostatin/GDF8 signaling and promote functional myoblast differentiation.
- Author
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Horbelt D, Boergermann JH, Chaikuad A, Alfano I, Williams E, Lukonin I, Timmel T, Bullock AN, and Knaus P
- Subjects
- Activin Receptors, Type II chemistry, Amino Acid Sequence, Animals, Binding Sites, Humans, Mice, Molecular Sequence Data, Myoblasts cytology, Myoblasts metabolism, Protein Binding, Sf9 Cells, Smad2 Protein metabolism, Smad3 Protein metabolism, Spodoptera, Transcription Factors metabolism, Activin Receptors, Type II metabolism, Cell Differentiation, Myoblasts drug effects, Myostatin pharmacology, Pyrazoles pharmacology, Pyrimidines pharmacology, Signal Transduction
- Abstract
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., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2015
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