Résumé :
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Dystrophin deficiency is the underlying molecular cause of progressive muscle weakness observed in Duchenne muscular dystrophy (DMD). Loss of functional dystrophin leads to elevated levels of intracellular Ca2+, a key step in the cellular pathology of DMD. Calpains are activated in dystrophin-deficient muscle, and their inhibition is regarded as a potential therapeutic approach. The contribution of the ubiquitin-proteasome system in muscle wasting conditions and the finding that its pharmacological inhibition mitigates the dystrophic phenotype in mdx mice qualify the proteasome as a potential target for therapeutic intervention in DMD Here we present evidence that uncontrolled Ca2+ influx into muscle cells similar to that observed in dystrophin-deficient muscle not only initiates calpain- but also proteasome-mediated proteolysis. Based on this finding we set out to optimize novel dual small-molecule inhibitors that inhibit both calpain as well as the proteasome in a cellular system with impaired Ca2+ homeostasis. Such dual calpain/proteasome inhibitors, when administered to mdx mice, significantly improve quantitative histological parameters For further assessment of the role of calpain inhibition, we crossed mdx mice with transgenic mice overexpressing the endogenous calpain inhibitor calpastatin. While our data show that proteolysis by calpain is strongly inhibited in the trangenic mdx mouse, this calpain inhibition alone does not ameliorate muscle histology. In conclusion, these results indicate that inhibition of the proteasome rather than calpain inhibition alone is required to show histological improvement in dystrophin deficient muscles.
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