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.

HIV-1 Nef Triggers Macrophage Fusion in a p61Hck- and Protease-Dependent Manner

“…Additionally, lysosomal proteases could modulate surface receptor activity and signaling involved in cell-cell fusion (53,68,69,(83)(84)(85). Lysosomal proteases have been implicated in the formation of myotubes (60,61) and found in the secretome of HIV-1-infected giant human macrophages (86). In the presence of protease inhibitors, the formation of MGCs is altered in Nef-expressing RAW264.7 cells or HIV-1-infected human macrophages.…”

“…7C). We wondered whether lysosome enzymes such as proteases might contribute to macrophage fusion, because they have been implicated in the formation of multinucleated myotubes (60,61). Therefore, we used a protease inhibitor mix, mostly non-cellpermeant, containing pepstatin A (inhibitor of aspartic proteases including cathepsin D), leupeptin (a broad inhibitor of cysteine proteases and cathepsin B), aprotinin (inhibitor of serine proteases), E64C (inhibitor of cysteine proteases such as cathepsins B, L, H, and K), and GM6001 (a broad metalloproteases inhibitor) (62)(63)(64).…”

Identification and Characterization of Lutheran Blood Group Glycoprotein as a New Substrate of Membrane-type 1 Matrix Metalloproteinase 1 (MT1-MMP)

“…Consistent with these functions, forced expression of MT1-MMP in tumor cells enhances behavior consistent with increased malignancy, such as rapid tumor growth, invasion, and metastasis (6). However, MT1-MMP is normally expressed in various types of cell and mice deficient in MT1-MMP expression (MT1 Ϫ/Ϫ ) display pleiotropic defects (7)(8)(9)(10). However, we as yet have only limited knowledge of the physiological substrates of MT1-MMP that could explain such pleiotropic effects.…”

Stem Cell Based Therapy for Muscular Dystrophies: Cell Types and Environmental Factors Influencing Their Efficacy

“…Myogenic cells have been reported to express various MMPs -MMP-1, -2, -3, -7, -9, -10, -14 and -16, either constitutively or after treatment with growth factors, cytokines or phorbol esters (Balcerzak et al, 2001;Caron et al, 1999;El Fahime et al, 2000;Guérin & Holland, 1995;Kherif et al, 1999;Lewis et al, 2000;Lluri & Jaworski, 2005;Nishimura et al, 2008;Ohtake et al, 2006). Cytokines and growth factors differentially modulate MMPs expression in myogenic cells.…”