Résumé :
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Laminopathies are a wide clinical spectrum of disorders caused by mutations in the LMNA gene encoding the A-type lamins. Some laminopathies like the Emery-Dreifuss muscular dystrophy (EDMD) specifically affect the striated muscle and are characterized by muscular dystrophy associated to dilated cardiomyopathy and conduction and/or rhythm defects (DCM-CD). A-type lamins, along with B-type lamins, delineate the lamina on the inner side of the nuclear envelope. They interact with numerous proteins of the nuclear envelope, DNA and transcription factors. Their exact role remains elusive: they are thought to participate in replication, transcription, chromatin organization and nuclear envelope structure. The mechanisms by which LMNA mutations, encoding ubiquitous proteins, cause disorders specifically affecting striated muscle remain to be elucidated. To analyse the pathomechanisms of LMNA mutations, Lmna knock-out and knock-in murine models have been created and some of them develop cardiac defects. Among these models, our KI-LmnaH222P mouse reproduces a mutation identified in patients with EDMD and develops a dilated cardiomyopathy with conduction system defects similar to that seen in patients. Transcriptome analysis of the mouse heart demonstrated the activation of the MAPK pathway before the onset of clinical signs of the cardiomyopathy. Analyses of the natural history of the disease in these mice indicate that the cardiac dysfunction seems mainly due to fibrosis progression. Assuming that fibrosis results from oxidative stress, we demonstrate that one-month oral treatment of KI-LmnaH222P mice with the anti-oxidant N-acetylcysteine (NAC), a glutathione precursor, slows down the progression of fibrosis and cardiac dysfunction through both blunting the adverse effects of the TNFR1/JNK pathway and preserving the survival Sirt1/TNFR2/ERK1/2 pathway. Studies are still necessary to further evaluate NAC as a potential therapeutic approach for the cardiomyopathy of our EDMD mouse model. 1. Inserm, U582, Institut de Myologie, Paris, (F-75013), France. 2. UPMC Univ Paris 06, UMR_S582, IFR14, Paris, (F-75013), France. 3. Inserm, U841, IMRB, Créteil, (F-94010), France. 4. Univ Paris XII-Val de Marne, Faculté de Médecine, Institut Mondor de Recherche Biomédicale, Créteil, (F-94010), France. 5. Department of Medicine and Department of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, New York, USA. 6. AP-HP, Groupe Hospitalier Pitié-Salpêtrière, U.F. Cardiogénétique et Myogénétique, Service de Biochimie Métabolique, Paris F-75013, France.
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