Résumé :
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Muscular dystrophies are characterized by fibrosis, a process leading to abnormal accumulation of materials of fibroblastic origin in the skeletal muscles as necrosis-regeneration cycles take place. Fibrosis results from alterations in a multifactorial balance involving cytokines and growth factors, expression of their receptors at the cells’ surface, oxidative stress, production of extracellular matrix components, release of matrix-metalloproteinases (MMPs) and of their endogenous inhibitors TIMPs (tissue inhibitors of MMPs), all collectively regulating extracellular matrix turnover and fibroblast invasiveness. Fibrosis severely impairs skeletal and cardiac muscle functions both in patients suffering from Duchenne muscular dystrophy (DMD) and in the mdx mouse, the most commonly used model for DMD. Published data indicate that green tea polyphenols (GTP) exhibit anti-fibrotic properties in several cell types and tissues, and pentoxifylline (PTX), a well-known inhibitor of TNF release, has been proposed to reduce fibrosis in the dystrophic mdx mouse. Treatment of primary cultures of mouse muscle at the myotube stage with GTP or PTX (2.5 to 25M) inhibited the expression and/or the release of the fibrosis modulators TNF TGF1, and PDGFBB. When needed, fibrosis was induced in the cultures with TNF or TGB1 (30ng/mL). GTP dose-dependently decreased both basal and TNF or TGB1-induced expression of smooth muscle actin (SMA, a marker for activated fibroblasts), collagen, TGF receptor type 2, and CTGF (connective tissue growth factor, a key mediator of TGF1 actions). As determined by zymography, the expression of pro- and active forms of MMP-2 and MMP-9 were not changed with GTP and PTX. However, the MMP-2 and MMP-9 gelatinase activity in the supernatants was significantly decreased and correlated with a marked elevation of TIMP-1 levels. Overall, PTX was less potent than GTP on these endpoints. Our results indicate that GTP profoundly alter the expression and/or the activity of proteins involved in the fibrogenic process.
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