1. Academic Validation
  2. Small molecules dorsomorphin and LDN-193189 inhibit myostatin/GDF8 signaling and promote functional myoblast differentiation

Small molecules dorsomorphin and LDN-193189 inhibit myostatin/GDF8 signaling and promote functional myoblast differentiation

  • J Biol Chem. 2015 Feb 6;290(6):3390-404. doi: 10.1074/jbc.M114.604397.
Daniel Horbelt 1 Jan H Boergermann 1 Apirat Chaikuad 2 Ivan Alfano 2 Eleanor Williams 2 Ilya Lukonin 1 Tobias Timmel 3 Alex N Bullock 2 Petra Knaus 4
Affiliations

Affiliations

  • 1 From the Institute for Chemistry-Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany.
  • 2 the Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, United Kingdom, and.
  • 3 the Muscle Research Unit, Experimental and Clinical Research Center, 13125 Berlin, Germany.
  • 4 From the Institute for Chemistry-Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany, knaus@chemie.fu-berlin.de.
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.

Keywords

Bone Morphogenetic Protein (BMP); Myogenesis; Myostatin; Serine/Threonine Protein Kinase; Small Molecule.

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