Titre :
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Fine-tuning in Ca2+ homeostasis underlies progression of cardiomyopathy in myocytes derived from genetically modified embryonic stem cells (abstract : congrès international de Myologie, 2005)
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contenu dans :
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Auteurs :
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Congrès international de myologie 2005 (International Congress of Myology 2005; 9-13 mai 2005; Nantes, France) ;
Grey C ;
Méry PF
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Type de document :
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Article
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Année de publication :
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2005
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Pages :
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p. 203
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Langues:
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Anglais
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Mots-clés :
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actine
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calcium
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cardiomyopathie hypertrophique
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cellule souche embryonnaire
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colloque
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équilibre calcique
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facteur Mef-2
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fibre musculaire cardiaque
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gène canal ionique
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immunofluorescence
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in vitro
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mutation génétique
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myocarde
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Résumé :
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Communication n° 34 Mutations of genes encoding ionic channels or contractile proteins are responsible for familial hypertrophic cardiomyopathies. Understanding the process of differentiation of cardiomyocytes carrying a mutated protein is a crucial step towards potential treatments of inherited cardiac disorders. Embryonic Stem (ES) cells which faithfully recapitulate in vitro the process of cardiac cell differentiation can be genetically modified to incorporate a mutation mimicking a cardiomyopathy. Embryonic Stem (ES) cell lines engineered to express a wild type (MLC2vGFP) or a mutated form (R58QMLC2vGFP) of ventricular myosin light chain 2 fused to GFP were differentiated into cardiomyocytes within embryoid bodies (EBs). Visualization of GFP combined with sarcomeric actinin immunofluorescence of EBs revealed that mutated MLC2v dramatically prevented myofibrillogenesis. Cardiomyocytes expressing wild type MLC2v featured spontaneous Ca2+ spiking but not those harboring the mutation. Expression of cardiac transcription factors Mef2c and Nkx2.5 was not affected by cell expression of mutated MLC2v. A dramatic decrease in expression of mRNAs -actin, MLC2a and MLC2v was observed in R58QMLC2vGFP EBs. This event??encoding was attributed to a failure of Mef2c to translocate into the nucleus, a Ca2+-dependent process. Expression in mutated cells of a constitutively active Ca2+- and calmodulin-dependent kinase II fully restored translocation of Mef2c into the nucleus and expression of mRNAs encoding sarcomeric proteins partially rescuing contractile activity of EBs. Alteration of Ca2+ homeostasis in mutated cardioblasts affects the transcriptional program of cardiac cell differentiation leading to a defect in myofibrillogenesis, and in turn in contractility. Genetically modified ES cells provide a unique cell model to determine abnormalities in Ca2+ homeostasis underlying progression of human cardiomyopathies.
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