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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.

Original publication

DOI

10.1074/jbc.M114.604397

Type

Journal article

Journal

J Biol Chem

Publication Date

06/02/2015

Volume

290

Pages

3390 - 3404

Keywords

Bone Morphogenetic Protein (BMP), Myogenesis, Myostatin, Serine/Threonine Protein Kinase, Small Molecule, Activin Receptors, Type II, Amino Acid Sequence, Animals, Binding Sites, Cell Differentiation, Humans, Mice, Molecular Sequence Data, Myoblasts, Myostatin, Protein Binding, Pyrazoles, Pyrimidines, Sf9 Cells, Signal Transduction, Smad2 Protein, Smad3 Protein, Spodoptera, Transcription Factors