title: Activation or inactivation of cardiac Akt/mTOR signaling diverges physiological from pathological hypertrophy.
abstract: Cardiomyocyte hypertrophy differs according to the stress exerted on the myocardium. While pressure overload-induced cardiomyocyte hypertrophy is associated with depressed contractile function, physiological hypertrophy after exercise training associates with preserved or increased inotropy. We determined the activation state of myocardial Akt signaling with downstream substrates and fetal gene reactivation in exercise-induced physiological and pressure overload-induced pathological hypertrophies. C57BL/6J mice were either treadmill trained for 6 weeks, 5 days/week, at 85-90% of maximal oxygen uptake (VO(2max)), or underwent transverse aortic constriction (TAC) for 1 or 8 weeks. Total and phosphorylated protein levels were determined with SDS-PAGE, and fetal genes by real-time RT-PCR. In the physiologically hypertrophied heart after exercise training, total Akt protein level was unchanged, but Akt was chronically hyperphosphorylated at serine 473. This was accompanied by activation of the mammalian target of rapamycin (mTOR), measured as phosphorylation of its two substrates: the ribosomal protein S6 kinase-1 (S6K1) and the eukaryotic translation initiation factor-4E binding protein-1 (4E-BP1). Exercise training did not reactivate the fetal gene program (beta-myosin heavy chain, atrial natriuretic factor, skeletal muscle actin). In contrast, pressure overload after TAC reactivated fetal genes already after 1 week, and partially inactivated the Akt/mTOR pathway and downstream substrates after 8 weeks. In conclusion, changes in opposite directions of the myocardial Akt/mTOR signal pathway appears to distinguish between physiological and pathological hypertrophies; exercise training associating with activation and pressure overload associating with inactivation of the Akt/mTOR pathway.
authors.affiliation: Institute of Biomedical and Life Sciences, University of Glasgow, UK. o.kemi@bio.gla.ac.uk
authors.forename: Ole Johan
authors.initials: OJ
authors.lastname: Kemi
authors.forename: Marcello
authors.initials: M
authors.lastname: Ceci
authors.forename: Ulrik
authors.initials: U
authors.lastname: Wisloff
authors.forename: Serena
authors.initials: S
authors.lastname: Grimaldi
authors.forename: Paolo
authors.initials: P
authors.lastname: Gallo
authors.forename: Godfrey L
authors.initials: GL
authors.lastname: Smith
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Condorelli
authors.forename: Oyvind
authors.initials: O
authors.lastname: Ellingsen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001013:Aorta, Thoracic / Q000503:physiopathology; D006332:Cardiomegaly / Q000503:physiopathology*; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D048429:Cell Size; D003251:Constriction, Pathologic / Q000503:physiopathology; D004452:Echocardiography; D004789:Enzyme Activation / Q000187:drug effects; D039642:Eukaryotic Initiation Factors; D005080:Exercise Test; D005260:Female; D006352:Heart Ventricles / Q000166:cytology; D006984:Hypertrophy / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010805:Physical Conditioning, Animal; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011897:Random Allocation; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D010750:Phosphoproteins; D012694:Serine; D011494:Protein Kinases; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus