title: Inhibition of the myostatin/Smad signaling pathway by short decorin-derived peptides.
abstract: Myostatin, also known as growth differentiation factor 8, is a member of the transforming growth factor-beta superfamily that has been shown to play a key role in the regulation of the skeletal muscle mass. Indeed, while myostatin deletion or loss of function induces muscle hypertrophy, its overexpression or systemic administration causes muscle atrophy. Since myostatin blockade is effective in increasing skeletal muscle mass, myostatin inhibitors have been actively sought after. Decorin, a member of the small leucine-rich proteoglycan family is a metalloprotein that was previously shown to bind and inactivate myostatin in a zinc-dependent manner. Furthermore, the myostatin-binding site has been shown to be located in the decorin N-terminal domain. In the present study, we investigated the anti-myostatin activity of short and soluble fragments of decorin. Our results indicate that the murine decorin peptides DCN48-71 and 42-65 are sufficient for inactivating myostatin in vitro. Moreover, we show that the interaction of mDCN48-71 to myostatin is strictly zinc-dependent. Binding of myostatin to activin type II receptor results in the phosphorylation of Smad2/3. Addition of the decorin peptide 48-71 decreased in a dose-dependent manner the myostatin-induced phosphorylation of Smad2 demonstrating thereby that the peptide inhibits the activation of the Smad signaling pathway. Finally, we found that mDCN48-71 displays a specificity towards myostatin, since it does not inhibit other members of the transforming growth factor-beta family.
authors: Unité de Technologies Chimiques et Biologiques pour la Santé, CNRS UMR8258-Inserm, U1022 - Université Paris Descartes, Chimie ParisTech, 75006 Paris, France.
authors: Nelly
authors: N
authors: El Shafey
authors: Unité de Technologies Chimiques et Biologiques pour la Santé, CNRS UMR8258-Inserm, U1022 - Université Paris Descartes, Chimie ParisTech, 75006 Paris, France.
authors: Mickaël
authors: M
authors: Guesnon
authors: Laboratoire de Biologie et Pharmacologie Appliquée, ENS Cachan, UMR8113 CNRS, IDA FR3242, 94230 Cachan, France.
authors: Françoise
authors: F
authors: Simon
authors: Laboratoire de Biologie et Pharmacologie Appliquée, ENS Cachan, UMR8113 CNRS, IDA FR3242, 94230 Cachan, France.
authors: Eric
authors: E
authors: Deprez
authors: Inserm, UMR 951, Université d'Evry Val d'Essonne, Genethon, 91000 Evry, France.
authors: Jérémie
authors: J
authors: Cosette
authors: Inserm, UMR 951, Université d'Evry Val d'Essonne, Genethon, 91000 Evry, France.
authors: Daniel
authors: D
authors: Stockholm
authors: Unité de Technologies Chimiques et Biologiques pour la Santé, CNRS UMR8258-Inserm, U1022 - Université Paris Descartes, Chimie ParisTech, 75006 Paris, France.
authors: Daniel
authors: D
authors: Scherman
authors: Unité de Technologies Chimiques et Biologiques pour la Santé, CNRS UMR8258-Inserm, U1022 - Université Paris Descartes, Chimie ParisTech, 75006 Paris, France.
authors: Pascal
authors: P
authors: Bigey
authors: Unité de Technologies Chimiques et Biologiques pour la Santé, CNRS UMR8258-Inserm, U1022 - Université Paris Descartes, Chimie ParisTech, 75006 Paris, France; Laboratoire de Conception et Application de Molécules Bioactives UMR7199 CNRS-Université de Strasbourg, LabEx Medalis, Faculté de Pharmacie, 67401 Illkirch, France. Electronic address: kichler@unistra.fr.
authors: Antoine
authors: A
authors: Kichler
mesh_terms: D058575:Decorin / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006801:Humans; D018482:Muscle, Skeletal / Q000378:metabolism*; D055435:Myostatin / Q000235:genetics*; D010455:Peptides / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D058575:Decorin; D016326:Extracellular Matrix Proteins; D055435:Myostatin; D010455:Peptides; D011509:Proteoglycans; D051785:Smad Proteins; D016212:Transforming Growth Factor beta
keywords: Decorin; Myostatin; Peptide; Small leucine rich proteoglycans; TGF-β superfamily