Skeletal muscle cell hypertrophy induced by inhibitors of metalloproteases; myostatin as a potential mediator

Cell growth and differentiation are controlled in many tissues by paracrine factors, which often require proteolytic processing for activation. Metall oproteases of the metzincin family, such as matrix metalloproteases and ADA Ms, recently have been shown to be involved in the shedding of growth facto rs, cytokines, and receptors. In the present study, we show that hydroxamat e-based inhibitors of metalloproteases (HIMPs), such as TAPI and BB-3103, i ncrease the fusion of C2C12 myoblasts and provoke myotube hypertrophy. HIMP s did not seem to effect hypertrophy via proteins that have previously been shown to regulate muscle growth in vitro, such as insulin-like growth fact or-I, calcineurin, and tumor necrosis factor-alpha. Instead, the proteolyti c maturation of myostatin (growth differentiation factor-8) seemed to be re duced in C2C12 cells treated with HIMPs, as suggested by the presence of no nprocessed myostatin precursor only in hypertrophic myotubes. Myostatin is a known negative regulator of skeletal muscle growth, belonging to the tran sforming growth factor-beta /bone morphogenetic protein superfamily. These results indicate that metalloproteases are involved in the regulation of sk eletal muscle growth and differentiation, that the proteolytic maturation o f myostatin in C2C12 cells may be directly or indirectly linked to the acti vity of some unidentified HIMP-sensitive metalloproteases, and that the lac k of myostatin processing on HIMP treatment may be a mediator of myotube hy pertrophy in this in vitro model.