Résumé :
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Autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD) is caused by mutations in the LMNA gene encoding A-type lamins, protein building blocks of the nuclear lamina. EDMD is characterized by muscle weakness and wasting in a humeroperoneal distribution and contractures of the elbows, neck extensor muscles and Achilles' tendons. Dilated cardiomyopathy occurs in virtually all cases of EDMD, which is characterized by left ventricle dilatation associated with impaired systolic function. Patients with EDMD eventually develop heart failure, rendering many in need of a cardiac transplant. Until recently, the prospects for improvement in the prevention and treatment of EDMD were limited by our lack of knowledge on the underlying pathogenesis. We recently made new discoveries that provided a coherent and testable model to explain the pathogenesis of EDMD. In LmnaH222P/H222P mice, a mouse model of EDMD, we found that abnormal activation of the ERK branch of the stress-activated MAP kinase cascade occurs in the heart, prior to the development of the cardiomyopathy. We then proposed the hypothesis that activation of the ERK branch of the MAP kinase signaling pathway underlies the pathogenesis of EDMD. To test our hypothesis, we used two separate in vivo approaches. First, we crossed LmnaH222P/H222P mice to Erk1 null mice to generate LmnaH222P/H222P mice deficient in this ERK isoform. We compared these mice to LmnaH222P/H222P/Erk1+/+ mice at 16 weeks of age, when LmnaH222P/H222P/Erk1+/+ mice have left ventricular dilatation and reduced ejection fraction (EF). Second, we administered small inhibitors of MEK, the kinase that phosphorylates ERK, to LmnaH222P/H222P mice from 16 weeks to 20 weeks. For the two approaches, we assessed the hearts by histology (Gomori's trichrome staining) and echocardiography. We also examined the expression of mRNAs encoding natriuretic peptide precursors (Nppa and Nppb) and collagens involved in myocardial fibrosis (Col1a1 and Col1a2). Inhibiting ERK signaling by both approaches significantly reduced myocardial fibrosis, associated with a decrease in Col1a1 and Col1a2 expression compared to controls. We also showed reduction in Nppa and Nppb expression in hearts of both LmnaH222P/H222P/Erk1-/- mice and LmnaH222P/H222P mice treated with a MEK inhibitor compared to controls. Both LmnaH222P/H222P/Erk1-/- and LmnaH222P/H222P mice treated with a MEK inhibitor had significant reductions of left ventricle dilatation and significantly greater than controls. EF improved by 20% in LmnaH222P/H222P mice treated with a MEK inhibitor and by 60% in LmnaH222P/H222P/Erk1-/- mice.Inhibiting ERK signaling halted left ventricular dilatation, increased EF and prevented myocardial fibrosis in LmnaH222P/H222P mice. These results provide proof of principle for ERK inhibition as a treatment for cardiomyopathy in EDMD.
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