title: Small molecules dorsomorphin and LDN-193189 inhibit myostatin/GDF8 signaling and promote functional myoblast differentiation.
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.
authors.affiliation: From the Institute for Chemistry-Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Horbelt
authors.affiliation: From the Institute for Chemistry-Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Boergermann
authors.affiliation: the Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, United Kingdom, and.
authors.forename: Apirat
authors.initials: A
authors.lastname: Chaikuad
authors.affiliation: the Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, United Kingdom, and.
authors.forename: Ivan
authors.initials: I
authors.lastname: Alfano
authors.affiliation: the Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, United Kingdom, and.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Williams
authors.affiliation: From the Institute for Chemistry-Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany.
authors.forename: Ilya
authors.initials: I
authors.lastname: Lukonin
authors.affiliation: the Muscle Research Unit, Experimental and Clinical Research Center, 13125 Berlin, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Timmel
authors.affiliation: the Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, United Kingdom, and.
authors.forename: Alex N
authors.initials: AN
authors.lastname: Bullock
authors.affiliation: From the Institute for Chemistry-Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany, knaus@chemie.fu-berlin.de.
authors.forename: Petra
authors.initials: P
authors.lastname: Knaus
mesh_terms: D030301:Activin Receptors, Type II / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D055435:Myostatin / Q000494:pharmacology*; D011485:Protein Binding; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D061987:Sf9 Cells; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D018411:Spodoptera; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C554430:LDN 193189; D055435:Myostatin; D011720:Pyrazoles; D011743:Pyrimidines; D051899:Smad2 Protein; D051900:Smad3 Protein; D014157:Transcription Factors; C516138:dorsomorphin; D030301:Activin Receptors, Type II; C425585:activin receptor type II-A
keywords: Bone Morphogenetic Protein (BMP); Myogenesis; Myostatin; Serine/Threonine Protein Kinase; Small Molecule