Résumé :
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Duchenne Muscular Dystrophy (DMD) patients show muscular weakness, that progresses towards paralysis and leads to death at age 20-30. DMD patients usually die in the third decade because of respiratory or cardiac failure. DMD is caused by mutations in the gene encoding dystrophin, a cytoskeletal protein that normally contributes to the stabilization of the muscle fibre membrane. In DMD, dystrophin is absent, leading to numerous cellular dysfunctions that culminate in muscle cell necrosis. In the mdx dystrophic mouse, both inflammation and oxidative stress have been identified as aggravating factors for the course of the disease. Dysfunctional calcium signalling via increased "store-operated Ca2+ channels" appears to be an initiating event in cell necrosis and we have shown that long-term exposure to the glucocorticoid prednisolone inhibits this influx. Steroids of the glucocorticoid type act mainly via their nuclear receptor, which is one of the over 2000 transcription factors controlling gene expression. Prednisolone treatment of mdx mice led to over 100 differentially regulated genes in their muscle showing that glucocorticoids confer their benefit to dystrophic muscle in a complex fashion, culminating in a switch to a more normal muscle fiber type (Fisher, Abraham et al. 2005). As mentioned, glucocorticoids are beneficial for dystrophic muscle (Hudecki, Pollina et al. 1993; Muntoni, Fisher et al. 2002; Merlini, Cicognani et al. 2003; Manzur, Kuntzer et al. 2008) but cause muscle wasting in normal muscle (Sheffield-Moore and Urban 2004). This positive effect on dystrophic muscle could be due to stimulation of anabolic or inhibition of catabolic processes. The latter include the inhibition of NF-kB function (Cai, Frantz et al. 2004; Clark 2007), which is activated by TNF. that has been shown to be important for disease manifestation in mdx mice (Grounds and Torrisi 2004; Radley, De Luca et al. 2007). Anabolic processes can be stimulated by the phosphatidyl inositol 3-kinase-AKT/PKB pathway (Failor, Desyatnikov et al. 2007), which is elevated in mdx muscle (Dogra, Changotra et al. 2006), possibly via stimulation of IGF-1, which stimulates the phosphatidyl inositol 3kinase-AKT/PKB pathway (Latres, Amini et al. 2005). Activation of this pathway has been shown to inhibit downstream atrogenes including MuRF1 and MAFbx (Latres, Amini et al. 2005). Finally, glucocorticoid action on normal muscle occurs also via the negative growth regulator myostatin (Gilson, Schakman et al. 2007). Another intriguing possibility is the involvement of phospholipase A2 (PLA2) as activation of the glucocorticoid receptor inhibits this enzyme. This inhibition occurs via transcriptional activation of lipocortin-1 (Flower 1981), now called annexin-1 which directly inhibits PLA2 (Croxtall, Choudhury et al. 1996; Willmott, Choudhury et al. 1997; Croxtall, Choudhary et al. 2000). Of note, the activity of PLA2 is 15-fold higher in DMD than in control muscle (Lindahl, Backman et al. 1995) and we have found that iPLA2. has a 2-3 fold higher expression level in mdx than in control muscle (Boittin, Petermann et al. 2006). Incubation of myotubes with therapeutic concentrations of a-methylprednisolone inhibits store-operated Ca2+ influx (Metzinger, Passaquin et al. 1995)Leijendekker, 1996 #3773; Passaquin, 1998 #7615). In addition, levels of annexin-1 were 6-fold lower in mdx as compared to control myotubes and treatment of these with 1 .M methylprednisolone led to an up-regulation of annexin-1 while downregulation of iPLA2. using RNAi lowered store-activated Ca2+ influx to a similar extent as methylprednisolone. It is tempting to assume that annexin-1 inhibits the overexpressed iPLA2. Supported by the Swiss Foundation of Research on Muscular Diseases, the Duchenne Parent Project (NL), the Association Française contre les Myopathies (AFM), and the Swiss National Science Foundation. Références : - Boittin, F.-X., O. Petermann, et al. (2006). "Ca2+-independent phospholipase A2 enhances store-operated Ca2+ entry in dystrophic skeletalmuscle fibers." J Cell Sci 119(18): 3733-3742. - Cai, D., J. D. Frantz, et al. (2004). "IKKbeta/NF-kappaB Activation Causes Severe Muscle Wasting in Mice." Cell 119(2): 285-298. - Clark, A. R. (2007). "Anti-inflammatory functions of glucocorticoid-induced genes." Molecular and Cellular Endocrinology 275(1-2): 79-97. - Croxtall, J. D., Q. Choudhary, et al. (2000). "Glucocorticoids act within minutes to inhibit recruitment of signalling factors to activated EGF receptors through a receptor-dependent, transcription-independent mechanism." Br. J. 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