Résumé :
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The contractile function of the heart in early postnatal development and in adult is fuelled by ATP generated mainly from fatty acid oxidation in mitochondria. Because the heart has a limited capacity to store or synthesize fatty acids, cellular fatty acid uptake and oxidation are tightly coupled and factors that control these gene networks are important regulators of cardiac function. Receptor-interacting protein 140 (RIP140) is a ligand-dependent cofactor for nuclear receptors that regulate sets of genes involved in metabolism. In RIP140-null mice, sets of genes promoting energy mobilization are upregulated in adipocytes and skeletal muscle where alteration in fibre type distribution towards more oxidative ones with increased mitochondrial number is observed too. In this regard, we hypothesized that ubiquitous expression of RIP140 in mice would lead to defects in metabolic tissues.The primary effect of RIP140 overexpression in transgenic (TG) mice is impaired postnatal heart function. There is rapid onset of cardiac hypertrophy and ventricular fibrosis (lines 34, 45, 51 compared to WT), detected microscopically, in male RIP140 TG mice from 4 weeks of age, resulting in 25% mortality by 5 months. RIP140 overexpression in the heart leads to decreased mitochondria state III and IV membrane potential and oxygen consumption. Quantitative PCR showed reduced expression of genes involved in mitochondrial activity and fatty acid metabolism many of which are known targets for PPARs and ERRs. This study demonstrates that RIP140 plays an important role in postnatal cardiac function and its implication in metabolic myopathies should be investigated further.
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