Résumé :
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Emery-Dreifuss muscular dystrophy (EDMD) is characterized by cardiac dysfunction and dilation associated with skeletal muscle defects. It is caused by mutations in the LMNA gene encoding the nuclear proteins lamin A/C that form a meshwork under the nuclear membrane. The LmnaH222P/H222P mouse model reproduces one of the mutations identified in EDMD patients and presents cardiac and skeletal muscle defects reminiscent of the disease. Left ventricle dysfunction and dilation in 7-month old female LmnaH222P/H222P mouse was associated with systemic and cardiac depletion in glutathione, elevation in oxidative stress marker (Malondealdehyde: MDA contents), secreted proinflammatory cytokine tumor necrosis factor (sTNF) and fibrosis. One-month oral NAC treatment prevented cardiac function and morphologic worsening assessed by echocardiography, normalized systemic glutathione, MDA, and sTNF contents. We explored the possible molecular mechanisms underlying the cardiac beneficial effects of NAC by focusing on ROS and sTNF-related signalling. Oxidative stress induced upregulation of the cardiac histone deacetylase Sirt1 mRNA in LmnaH222P/H222P mouse. This corroborated with decreased acetylation of histone-3 and downstream caspase-dependant death, illustrated by the reduced processing of pro-apoptotic protein BID and caspase-3. MAPKinase pathways were activated in 7-month old LmnaH222P/H222P mouse : 1) ERK1/2 phosphorylation was associated with TNFR2 protein upregulation, both participating to survival pathway scheduling ; 2) Increased JNK phosphorylation correlated with TNFR1 protein upregulation, both illustrating deleterious response. NAC treatment decreased the severity of the cardiac phenotype induced by the LmnaH222P mutation by both blunting adverse TNFR1/JNK pathway and preserving survival Sirt1/TNFR2/ERK1/2 pathway.
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