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1 The Burnham Institute, La Jolla, California 92037; 2 Institut National de la Santé et de la Recherche Médicale-Institut National de la Recherche Agronomique U418, Communications Cellulaires et Différenciation, Hôpital Debrousse, 69322 Lyon, France; 3 Research Administration, Immunex Corporation, Seattle, Washington 98101; and 4 Centre National de la Recherche Scientifique UPR 2163, Physiologie Moléculaire et Cellulaire, Centre Hospitalier Universitaire Purpan, 31059 Toulouse Cedex 03, France
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 C2C12 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-
. Instead, the proteolytic maturation of myostatin (growth differentiation factor-8) seemed to be reduced in
C2C12 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-
/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 C2C12 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.
metalloendopeptidases; protease inhibitor; growth and differentiation factor-8
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