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First published online 22 August 2006
doi: 10.1242/jcs.03158
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Research Article |
1 Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
2 Laboratory of Applied Genetics, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, 113-8675, Japan
* Author for correspondence (e-mail: mseiki{at}ims.u-tokyo.ac.jp)
Accepted 4 July 2006
Sequential activation of muscle-specific transcription factors is the critical basis for myogenic differentiation. However, the complexity of this process does not exclude the possibility that other molecules and systems are regulatory as well. We observed that myogenic differentiation proceeded through three distinct stages of proliferation, elongation and fusion, which are distinguishable by their cellular morphologies and gene expression patterns of proliferation- and differentiation-specific markers. Treatment of the differentiating myoblasts with inhibitors of matrix metalloproteinases (MMPs) revealed that MMP activity at the elongation stage is a critical prerequisite to complete the successive myoblast cell fusion. The MMP regulated the myogenic differentiation independently from the genetic program that governs expression of the myogenic genes. Membrane-type 1 matrix metalloproteinase (MT1-MMP) was identified as a major contributor to this checkpoint for morphological differentiation and degraded fibronectin, a possible inhibitory factor for myogenic cell fusion. A MT1-MMP deficiency caused similar myogenic impediments forming smaller myofibers in situ. Additionally, the mutant mice demonstrated some central nucleation of the myofibers typically found in muscular dystrophy and MT1-MMP was found to cleave laminin-2/4 in the basement membrane. Thus, MT1-MMP is a new multilateral regulator for muscle differentiation and maintenance through processing of stage-specific distinct ECM substrates.
Key words: MT1-MMP, ECM remodeling, Myogenesis, Myopathy
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