title: Enhanced cardiac Akt/protein kinase B signaling contributes to pathological cardiac hypertrophy in part by impairing mitochondrial function via transcriptional repression of mitochondrion-targeted nuclear genes.
abstract: Sustained Akt activation induces cardiac hypertrophy (LVH), which may lead to heart failure. This study tested the hypothesis that Akt activation contributes to mitochondrial dysfunction in pathological LVH. Akt activation induced LVH and progressive repression of mitochondrial fatty acid oxidation (FAO) pathways. Preventing LVH by inhibiting mTOR failed to prevent the decline in mitochondrial function, but glucose utilization was maintained. Akt activation represses expression of mitochondrial regulatory, FAO, and oxidative phosphorylation genes in vivo that correlate with the duration of Akt activation in part by reducing FOXO-mediated transcriptional activation of mitochondrion-targeted nuclear genes in concert with reduced signaling via peroxisome proliferator-activated receptor α (PPARα)/PGC-1α and other transcriptional regulators. In cultured myocytes, Akt activation disrupted mitochondrial bioenergetics, which could be partially reversed by maintaining nuclear FOXO but not by increasing PGC-1α. Thus, although short-term Akt activation may be cardioprotective during ischemia by reducing mitochondrial metabolism and increasing glycolysis, long-term Akt activation in the adult heart contributes to pathological LVH in part by reducing mitochondrial oxidative capacity.
authors.affiliation: Program in Molecular Medicine and Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, Utah, USA Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Wende
authors.affiliation: Program in Molecular Medicine and Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, Utah, USA Department of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: O'Neill
authors.affiliation: Program in Molecular Medicine and Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, Utah, USA Heart Center, Cardiology and Angiology I, Freiburg University, Freiburg, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Bugger
authors.affiliation: Program in Molecular Medicine and Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, Utah, USA Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Riehle
authors.affiliation: Program in Molecular Medicine and Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Tuinei
authors.affiliation: Program in Molecular Medicine and Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Buchanan
authors.affiliation: Program in Molecular Medicine and Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, Utah, USA Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Tsushima
authors.affiliation: Program in Molecular Medicine and Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Program in Molecular Medicine and Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Pilar
authors.initials: P
authors.lastname: Caro
authors.affiliation: Program in Molecular Medicine and Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, Utah, USA Diabetes Institute at Ohio University, Heritage College of Osteopathic Medicine/Specialty Medicine, Athens, Ohio, USA.
authors.forename: Aili
authors.initials: A
authors.lastname: Guo
authors.affiliation: Program in Molecular Medicine and Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Crystal
authors.initials: C
authors.lastname: Sloan
authors.affiliation: Program in Molecular Medicine and Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Bum Jun
authors.initials: BJ
authors.lastname: Kim
authors.affiliation: Program in Molecular Medicine and Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wang
authors.affiliation: Program in Molecular Medicine and Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, Utah, USA Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Renata O
authors.initials: RO
authors.lastname: Pereira
authors.affiliation: Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: McCrory
authors.affiliation: Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Brenna G
authors.initials: BG
authors.lastname: Nye
authors.affiliation: Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Gloria A
authors.initials: GA
authors.lastname: Benavides
authors.affiliation: Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Victor M
authors.initials: VM
authors.lastname: Darley-Usmar
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Shioi
authors.affiliation: Department of Population Health and Reproduction, University of California, Davis, School of Veterinary Medicine, Davis, California, USA.
authors.forename: Bart C
authors.initials: BC
authors.lastname: Weimer
authors.affiliation: Program in Molecular Medicine and Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, Utah, USA Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA DRCAdmin@uiowa.edu.
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006019:Glycolysis; D006321:Heart / Q000502:physiology; D006439:Hemodynamics; D006984:Hypertrophy; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D032342:Muscle Cells / Q000166:cytology; D010100:Oxygen / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D040901:Proteomics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D019076:Transgenes
chemical_list: D005227:Fatty Acids; D047493:PPAR alpha; D000255:Adenosine Triphosphate; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D010100:Oxygen