title: Cardiac mTOR complex 2 preserves ventricular function in pressure-overload hypertrophy.
abstract: OBJECTIVE
  Mammalian target of rapamycin (mTOR), a central regulator of growth and metabolism, has tissue-specific functions depending on whether it is part of mTOR complex 1 (mTORC1) or mTORC2. We have previously shown that mTORC1 is required for adaptive cardiac hypertrophy and maintenance of function under basal and pressure-overload conditions. In the present study, we aimed to identify functions of mTORC2 in the heart.
  
  
  RESULTS
  Using tamoxifen-inducible cardiomyocyte-specific gene deletion, we generated mice deficient for cardiac rapamycin-insensitive companion of mTOR (rictor), an essential and specific component of mTORC2. Under basal conditions, rictor deficiency did not affect cardiac growth and function in young mice and also had no effects in adult mice. However, transverse aortic constriction caused dysfunction in the rictor-deficient hearts, whereas function was maintained in controls after 1 week of pressure overload. Adaptive increases in cardiac weight and cardiomyocyte cross-sectional area, fibrosis, and hypertrophic and metabolic gene expression were not different between the rictor-deficient and control mice. In control mice, maintained function was associated with increased protein levels of rictor, protein kinase C (PKC)βII, and PKCδ, whereas rictor ablation abolished these increases. Rictor deletion also significantly decreased PKCε at baseline and after pressure overload. Our data suggest that reduced PKCε and the inability to increase PKCβII and PKCδ abundance are, in accordance with their known function, responsible for decreased contractile performance of the rictor-deficient hearts.
  
  
  CONCLUSIONS
  Our study demonstrates that mTORC2 is implicated in maintaining contractile function of the pressure-overloaded male mouse heart.
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.affiliation: Department of Biomedicine, University of Basel and University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland.
authors.forename: Lifen
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Biomedicine, University of Basel and University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Morandi
authors.affiliation: Department of Biomedicine, University of Basel and University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland.
authors.forename: Laura
authors.initials: L
authors.lastname: Pentassuglia
authors.affiliation: Department of Biomedicine, University of Basel and University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Heim
authors.affiliation: Department of Biomedicine, University of Basel and University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland.
authors.forename: Sonia
authors.initials: S
authors.lastname: Lebboukh
authors.affiliation: Department of Medicine and Cardiovascular Assessment Facility, University of Lausanne Medical School, Lausanne, Switzerland.
authors.forename: Corinne
authors.initials: C
authors.lastname: Berthonneche
authors.affiliation: Department of Medicine and Cardiovascular Assessment Facility, University of Lausanne Medical School, Lausanne, Switzerland.
authors.forename: Thierry
authors.initials: T
authors.lastname: Pedrazzini
authors.affiliation: Department of Biomedicine, University of Basel and University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland.
authors.forename: Beat A
authors.initials: BA
authors.lastname: Kaufmann
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hall
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Rüegg
authors.affiliation: Department of Biomedicine, University of Basel and University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland marijke.brink@unibas.ch.
authors.forename: Marijke
authors.initials: M
authors.lastname: Brink
mesh_terms: D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000503:physiopathology*; D002352:Carrier Proteins / Q000502:physiology; D005355:Fibrosis; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000502:physiology*; D009206:Myocardium / Q000473:pathology; D010750:Phosphoproteins / Q000502:physiology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000032:analysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D016276:Ventricular Function / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C508191:proline-rich Akt substrate, 40 kDa protein, mouse; C525637:rictor protein, mouse; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D011493:Protein Kinase C
keywords: Heart failure; Hypertrophy; Metabolism; Signal transduction