Identification of decorin derived peptides with a zinc dependent anti-myostatin activity

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 IC50 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.