Cell growth and differentiation are controlled in many tissues by paracrine factors, which often require proteolytic processing for activation.
Metalloproteases of the metzincin family, such as matrix
metalloproteases and ADAMs, recently have been shown to be involved in the shedding of
growth factors,
cytokines, and receptors. In the present study, we show that hydroxamate-based inhibitors of
metalloproteases (HIMPs), such as TAPI and
BB-3103, increase the fusion of C(2)C(12) myoblasts and provoke myotube
hypertrophy. HIMPs did not seem to effect
hypertrophy via
proteins that have previously been shown to regulate muscle growth in vitro, such as
insulin-like growth factor-I,
calcineurin, and
tumor necrosis factor-alpha. Instead, the proteolytic maturation of
myostatin (
growth differentiation factor-8) seemed to be reduced in C(2)C(12) cells treated with HIMPs, as suggested by the presence of nonprocessed
myostatin precursor only in hypertrophic myotubes.
Myostatin is a known negative regulator of skeletal muscle growth, belonging to the
transforming growth factor-beta/
bone morphogenetic protein superfamily. These results indicate that
metalloproteases are involved in the regulation of skeletal muscle growth and differentiation, that the proteolytic maturation of
myostatin in C(2)C(12) cells may be directly or indirectly linked to the activity of some unidentified HIMP-sensitive
metalloproteases, and that the lack of
myostatin processing on HIMP treatment may be a mediator of myotube
hypertrophy in this in vitro model.