Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice.

Détails

ID Serval
serval:BIB_92C6A4760279
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice.
Périodique
Circulation
Auteur(s)
Shende P., Plaisance I., Morandi C., Pellieux C., Berthonneche C., Zorzato F., Krishnan J., Lerch R., Hall M.N., Rüegg M.A., Pedrazzini T., Brink M.
ISSN
1524-4539 (Electronic)
ISSN-L
0009-7322
Statut éditorial
Publié
Date de publication
2011
Volume
123
Numéro
10
Pages
1073-1082
Langue
anglais
Résumé
Background- 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. Methods and Results- We generated mice with deficient myocardial mTORC1 activity by targeted ablation of raptor, 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. Conclusions- 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.
Pubmed
Web of science
Création de la notice
07/04/2011 9:58
Dernière modification de la notice
20/08/2019 15:55
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