Abstract
Myostatin, a TGF-β superfamily member, is a negative regulator of muscle growth. Here we describe how myostatin activity is regulated by syndecan-4, a ubiquitous transmembrane heparan sulfate proteoglycan. During muscle regeneration the levels of both syndecan-4 and promyostatin decline gradually after a sharp increase, concurrently with the release of mature myostatin. Promyostatin and syndecan-4 co-immunoprecipitate, and the interaction is heparinase-sensitive. ShRNA-mediated silencing of syndecan-4 reduces C2C12 myoblast proliferation via blocking the progression from G1- to S-phase of the cell cycle, which is accompanied by elevated levels of myostatin and p21(Waf1/Cip1), and decreases in cyclin E and cyclin D1 expression. Our results suggest that syndecan-4 functions as a reservoir for promyostatin regulating the local bioavailability of mature myostatin.