title: Multifunctional roles of MT1-MMP in myofiber formation and morphostatic maintenance of skeletal muscle.
abstract: 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.
authors.affiliation: Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Ohtake
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tojo
authors.forename: Motoharu
authors.initials: M
authors.lastname: Seiki
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002459:Cell Fusion; D002478:Cells, Cultured; D005353:Fibronectins / Q000378:metabolism; D005786:Gene Expression Regulation; D007797:Laminin / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D053504:Matrix Metalloproteinases, Membrane-Associated / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D024510:Muscle Development / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology* / Q000378:metabolism* / Q000502:physiology; D032448:Myoblasts, Skeletal / Q000166:cytology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics
chemical_list: D005353:Fibronectins; D007797:Laminin; D012333:RNA, Messenger; D019716:Tissue Inhibitor of Metalloproteinase-2; D053504:Matrix Metalloproteinases, Membrane-Associated; D020778:Matrix Metalloproteinase 2