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

Cell growthand differentiation are controlled in many tissues by paracrinefactors, which often require proteolytic processing for activation.Metalloproteases of the metzincin family, such as matrixmetalloproteases and ADAMs, recently have been shown to be involved inthe shedding of growth factors, cytokines, and receptors. In thepresent study, we show that hydroxamate-based inhibitors ofmetalloproteases (HIMPs), such as TAPI and BB-3103, increase the fusionof C₂C₁₂ myoblasts and provoke myotubehypertrophy. HIMPs did not seem to effect hypertrophy via proteins thathave previously been shown to regulate muscle growth in vitro, such asinsulin-like growth factor-I, calcineurin, and tumor necrosis factor-. Instead, the proteolytic maturation of myostatin (growth differentiation factor-8) seemed to be reduced inC₂C₁₂ cells treated with HIMPs, as suggested bythe presence of nonprocessed myostatin precursor only in hypertrophicmyotubes. Myostatin is a known negative regulator of skeletal musclegrowth, belonging to the transforming growth factor-/bonemorphogenetic protein superfamily. These results indicate thatmetalloproteases are involved in the regulation of skeletalmuscle growth and differentiation, that the proteolytic maturation ofmyostatin in C₂C₁₂ cells may be directly orindirectly linked to the activity of some unidentified HIMP-sensitivemetalloproteases, and that the lack of myostatin processing on HIMPtreatment may be a mediator of myotube hypertrophy in this in vitro model.