title: Identification of decorin derived peptides with a zinc dependent anti-myostatin activity.
abstract: Decorin is a member of the small leucine-rich proteoglycan family and it is a component of the extracellular matrix. Decorin was previously shown to bind different molecules, including myostatin, in a zinc-dependent manner. Here, we investigated in detail the anti-myostatin activity of decorin and fragments thereof. We show that this protein displays in vitro anti-myostatin activities with an IC(50) of 2.3 × 10(-8)M. After intramuscular injection of decorin in dystrophic mdx and γ-sarcoglycan(-/-) mice, we observed a significant increase of the muscle mass and this effect was maximal 18 days after administration. Further, we show that the myostatin-binding site is located in the N-terminal domain of decorin. In fact, a peptide encompassing the 31-71 sequence retains full myostatin binding capacity and intramuscular injection of the peptide induces muscle hypertrophy. The evaluation of three additional peptides suggests a crucial role of the four cysteines within the conserved CX3CXCX6C motif of class I of the small leucine-rich proteoglycans. Altogether, our results show that the N-terminal domain of decorin is sufficient for the binding to myostatin and they underscore the crucial role for this interaction of zinc and the cysteine cluster.
authors.affiliation: Genethon, BP60, 91002 Evry Cedex, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Guiraud
authors.forename: Laetitia
authors.initials: L
authors.lastname: van Wittenberghe
authors.forename: Christophe
authors.initials: C
authors.lastname: Georger
authors.forename: Daniel
authors.initials: D
authors.lastname: Scherman
authors.forename: Antoine
authors.initials: A
authors.lastname: Kichler
mesh_terms: D000818:Animals; D058575:Decorin / Q000378:metabolism / Q000494:pharmacology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D051379:Mice; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects; D009135:Muscular Diseases / Q000188:drug therapy*; D055435:Myostatin / Q000037:antagonists & inhibitors*; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000502:physiology; D011509:Proteoglycans / Q000494:pharmacology; D015032:Zinc / Q000378:metabolism*
chemical_list: D058575:Decorin; D016326:Extracellular Matrix Proteins; D055435:Myostatin; D010455:Peptides; D011509:Proteoglycans; D015032:Zinc