Cardiac Raptor Ablation Impairs Adaptive Hypertrophy, Alters Metabolic Gene Expression, and Causes Heart Failure in Mice
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- Pankaj Shende
- From the Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland (P.S., I.P., C.M., F.Z., M.B.); Medical Research Foundation and Cardiology Division, University of Geneva and University Hospital Geneva, Geneva, Switzerland (C.P., R.L.); Cardiovascular Assessment Facility, University of Lausanne Medical School, Lausanne, Switzerland (C.B.); Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland (T.P.); ETH Zurich, Zurich,...
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- Isabelle Plaisance
- From the Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland (P.S., I.P., C.M., F.Z., M.B.); Medical Research Foundation and Cardiology Division, University of Geneva and University Hospital Geneva, Geneva, Switzerland (C.P., R.L.); Cardiovascular Assessment Facility, University of Lausanne Medical School, Lausanne, Switzerland (C.B.); Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland (T.P.); ETH Zurich, Zurich,...
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- Christian Morandi
- From the Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland (P.S., I.P., C.M., F.Z., M.B.); Medical Research Foundation and Cardiology Division, University of Geneva and University Hospital Geneva, Geneva, Switzerland (C.P., R.L.); Cardiovascular Assessment Facility, University of Lausanne Medical School, Lausanne, Switzerland (C.B.); Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland (T.P.); ETH Zurich, Zurich,...
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- Corinne Pellieux
- From the Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland (P.S., I.P., C.M., F.Z., M.B.); Medical Research Foundation and Cardiology Division, University of Geneva and University Hospital Geneva, Geneva, Switzerland (C.P., R.L.); Cardiovascular Assessment Facility, University of Lausanne Medical School, Lausanne, Switzerland (C.B.); Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland (T.P.); ETH Zurich, Zurich,...
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- Corinne Berthonneche
- From the Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland (P.S., I.P., C.M., F.Z., M.B.); Medical Research Foundation and Cardiology Division, University of Geneva and University Hospital Geneva, Geneva, Switzerland (C.P., R.L.); Cardiovascular Assessment Facility, University of Lausanne Medical School, Lausanne, Switzerland (C.B.); Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland (T.P.); ETH Zurich, Zurich,...
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- Francesco Zorzato
- From the Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland (P.S., I.P., C.M., F.Z., M.B.); Medical Research Foundation and Cardiology Division, University of Geneva and University Hospital Geneva, Geneva, Switzerland (C.P., R.L.); Cardiovascular Assessment Facility, University of Lausanne Medical School, Lausanne, Switzerland (C.B.); Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland (T.P.); ETH Zurich, Zurich,...
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- Jaya Krishnan
- From the Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland (P.S., I.P., C.M., F.Z., M.B.); Medical Research Foundation and Cardiology Division, University of Geneva and University Hospital Geneva, Geneva, Switzerland (C.P., R.L.); Cardiovascular Assessment Facility, University of Lausanne Medical School, Lausanne, Switzerland (C.B.); Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland (T.P.); ETH Zurich, Zurich,...
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- René Lerch
- From the Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland (P.S., I.P., C.M., F.Z., M.B.); Medical Research Foundation and Cardiology Division, University of Geneva and University Hospital Geneva, Geneva, Switzerland (C.P., R.L.); Cardiovascular Assessment Facility, University of Lausanne Medical School, Lausanne, Switzerland (C.B.); Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland (T.P.); ETH Zurich, Zurich,...
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- Michael N. Hall
- From the Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland (P.S., I.P., C.M., F.Z., M.B.); Medical Research Foundation and Cardiology Division, University of Geneva and University Hospital Geneva, Geneva, Switzerland (C.P., R.L.); Cardiovascular Assessment Facility, University of Lausanne Medical School, Lausanne, Switzerland (C.B.); Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland (T.P.); ETH Zurich, Zurich,...
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- Markus A. Rüegg
- From the Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland (P.S., I.P., C.M., F.Z., M.B.); Medical Research Foundation and Cardiology Division, University of Geneva and University Hospital Geneva, Geneva, Switzerland (C.P., R.L.); Cardiovascular Assessment Facility, University of Lausanne Medical School, Lausanne, Switzerland (C.B.); Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland (T.P.); ETH Zurich, Zurich,...
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- Thierry Pedrazzini
- From the Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland (P.S., I.P., C.M., F.Z., M.B.); Medical Research Foundation and Cardiology Division, University of Geneva and University Hospital Geneva, Geneva, Switzerland (C.P., R.L.); Cardiovascular Assessment Facility, University of Lausanne Medical School, Lausanne, Switzerland (C.B.); Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland (T.P.); ETH Zurich, Zurich,...
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- Marijke Brink
- From the Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland (P.S., I.P., C.M., F.Z., M.B.); Medical Research Foundation and Cardiology Division, University of Geneva and University Hospital Geneva, Geneva, Switzerland (C.P., R.L.); Cardiovascular Assessment Facility, University of Lausanne Medical School, Lausanne, Switzerland (C.B.); Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland (T.P.); ETH Zurich, Zurich,...
書誌事項
- 公開日
- 2011-03-15
- DOI
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- 10.1161/circulationaha.110.977066
- 公開者
- Ovid Technologies (Wolters Kluwer Health)
この論文をさがす
説明
<jats:sec> <jats:title>Background—</jats:title> <jats:p>Cardiac hypertrophy involves growth responses to a variety of stimuli triggered by increased workload. It is an independent risk factor for heart failure and sudden death. Mammalian target of rapamycin (mTOR) plays a key role in cellular growth responses by integrating growth factor and energy status signals. It is found in 2 structurally and functionally distinct multiprotein complexes called mTOR complex (mTORC) 1 and mTORC2. The role of each of these branches of mTOR signaling in the adult heart is currently unknown.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p> We generated mice with deficient myocardial mTORC1 activity by targeted ablation of <jats:italic>raptor</jats:italic> , which encodes an essential component of mTORC1, during adulthood. At 3 weeks after the deletion, atrial and brain natriuretic peptides and β-myosin heavy chain were strongly induced, multiple genes involved in the regulation of energy metabolism were altered, but cardiac function was normal. Function deteriorated rapidly afterward, resulting in dilated cardiomyopathy and high mortality within 6 weeks. Aortic banding–induced pathological overload resulted in severe dilated cardiomyopathy already at 1 week without a prior phase of adaptive hypertrophy. The mechanism involved a lack of adaptive cardiomyocyte growth via blunted protein synthesis capacity, as supported by reduced phosphorylation of ribosomal S6 kinase 1 and 4E-binding protein 1. In addition, reduced mitochondrial content, a shift in metabolic substrate use, and increased apoptosis and autophagy were observed. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p>Our results demonstrate an essential function for mTORC1 in the heart under physiological and pathological conditions and are relevant for the understanding of disease states in which the insulin/insulin-like growth factor signaling axis is affected such as diabetes mellitus and heart failure or after cancer therapy.</jats:p> </jats:sec>
収録刊行物
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- Circulation
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Circulation 123 (10), 1073-1082, 2011-03-15
Ovid Technologies (Wolters Kluwer Health)