Document Detail


Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice.
MedLine Citation:
PMID:  21357822     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Pankaj Shende; Isabelle Plaisance; Christian Morandi; Corinne Pellieux; Corinne Berthonneche; Francesco Zorzato; Jaya Krishnan; René Lerch; Michael N Hall; Markus A Rüegg; Thierry Pedrazzini; Marijke Brink
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-02-28
Journal Detail:
Title:  Circulation     Volume:  123     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-03-15     Completed Date:  2011-06-02     Revised Date:  2013-09-30    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1073-82     Citation Subset:  AIM; IM    
Affiliation:
Department of Biomedicine, University of Basel and University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis
Atrial Natriuretic Factor / analysis,  metabolism
Autophagy
Cardiomegaly / genetics*,  physiopathology*
Carrier Proteins / genetics*,  metabolism,  physiology*
Energy Metabolism / genetics,  physiology
Gene Expression / physiology
Heart Failure / etiology*,  genetics
Heart Rate / physiology*
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria, Heart / metabolism,  physiology
Myosin Heavy Chains / analysis,  metabolism
Natriuretic Peptide, Brain / analysis,  metabolism
Nonmuscle Myosin Type IIB / analysis,  metabolism
Phosphoproteins / metabolism
Phosphorylation
Ribosomal Protein S6 Kinases, 90-kDa / metabolism
Chemical
Reg. No./Substance:
0/Carrier Proteins; 0/Eif4ebp1 protein, mouse; 0/Myosin Heavy Chains; 0/Phosphoproteins; 0/Rptor protein, mouse; 114471-18-0/Natriuretic Peptide, Brain; 85637-73-6/Atrial Natriuretic Factor; EC 2.7.11.1/Ribosomal Protein S6 Kinases, 90-kDa; EC 2.7.11.1/Rps6ka1 protein, mouse; EC 3.6.1.-/Nonmuscle Myosin Type IIB; EC 3.6.1.-/nonmuscle myosin type IIB heavy chain

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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