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| Item Type: | Article |
|---|---|
| Title: | Small molecules dorsomorphin and LDN-193189 inhibit myostatin/GDF8 signaling and promote functional myoblast differentiation |
| Creators Name: | Horbelt, D. and Boergermann, J.H. and Chaikuad, A. and Alfano, I. and Williams, E. and Lukonin, I. and Timmel, T. and Bullock, A.N. and Knaus, P. |
| 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 type 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 rescue 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. |
| Keywords: | GDF8, Myostatin, ActRII, Dorsomorphin, LDN-193189, Myogenesis, Animals, Mice, Spodoptera |
| Source: | Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Volume: | 290 |
| Number: | 6 |
| Page Range: | 3390-3404 |
| Date: | 6 February 2015 |
| Official Publication: | https://doi.org/10.1074/jbc.M114.604397 |
| PubMed: | View item in PubMed |
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