title: Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice.
abstract: 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.
  
  
  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.affiliation: Department of Biomedicine, University of Basel and University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Shende
authors.forename: Isabelle
authors.initials: I
authors.lastname: Plaisance
authors.forename: Christian
authors.initials: C
authors.lastname: Morandi
authors.forename: Corinne
authors.initials: C
authors.lastname: Pellieux
authors.forename: Corinne
authors.initials: C
authors.lastname: Berthonneche
authors.forename: Francesco
authors.initials: F
authors.lastname: Zorzato
authors.forename: Jaya
authors.initials: J
authors.lastname: Krishnan
authors.forename: René
authors.initials: R
authors.lastname: Lerch
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hall
authors.forename: Markus A
authors.initials: MA
authors.lastname: Rüegg
authors.forename: Thierry
authors.initials: T
authors.lastname: Pedrazzini
authors.forename: Marijke
authors.initials: M
authors.lastname: Brink
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D009320:Atrial Natriuretic Factor / Q000032:analysis / Q000378:metabolism; D001343:Autophagy; D006332:Cardiomegaly / Q000235:genetics* / Q000503:physiopathology*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D018797:Cell Cycle Proteins; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology; D039642:Eukaryotic Initiation Factors; D015870:Gene Expression / Q000502:physiology; D006333:Heart Failure / Q000209:etiology* / Q000235:genetics; D006339:Heart Rate / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism / Q000502:physiology; D018995:Myosin Heavy Chains / Q000032:analysis / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000032:analysis / Q000378:metabolism; D024501:Nonmuscle Myosin Type IIB / Q000032:analysis / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D000076223:Regulatory-Associated Protein of mTOR; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D010750:Phosphoproteins; D000076223:Regulatory-Associated Protein of mTOR; C540162:Rptor protein, mouse; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D024501:Nonmuscle Myosin Type IIB; C103815:nonmuscle myosin type IIB heavy chain; D018995:Myosin Heavy Chains