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Publication Abstract from PubMed

GDF8, or myostatin, is a member of the TGF-beta 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.

Small Molecules Dorsomorphin and LDN-193189 Inhibit Myostatin/GDF8 Signaling and Promote Functional Myoblast Differentiation.,Horbelt D, Boergermann JH, Chaikuad A, Alfano I, Williams E, Lukonin I, Timmel T, Bullock AN, Knaus P J Biol Chem. 2014 Nov 3. pii: jbc.M114.604397. PMID:25368322^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.