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

Adam R Wende; Brian T O'Neill; Heiko Bugger; Christian Riehle; Joseph Tuinei; Jonathan Buchanan; Kensuke Tsushima; Li Wang; Pilar Caro; Aili Guo; Crystal Sloan; Bum Jun Kim; Xiaohui Wang; Renata O Pereira; Mark A McCrory; Brenna G Nye; Gloria A Benavides; Victor M Darley-Usmar; Tetsuo Shioi; Bart C Weimer; E Dale Abel

doi:10.1128/MCB.01109-14

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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

Journal article

Peer reviewed

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

Adam R Wende, Brian T O'Neill, Heiko Bugger, Christian Riehle, Joseph Tuinei, Jonathan Buchanan, Kensuke Tsushima, Li Wang, Pilar Caro, Aili Guo, …

Molecular and cellular biology, Vol.35(5), pp.831-846

03/2015

DOI: 10.1128/MCB.01109-14

PMCID: PMC4323486

PMID: 25535334

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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.

Hemodynamics

Proteomics

Signal Transduction

Heart - physiology

Gene Expression Regulation

Male

Gene Expression Profiling

Mitochondria - metabolism

Oxygen - metabolism

Muscle Cells - cytology

Animals

Cell Nucleus - metabolism

Adenosine Triphosphate - metabolism

Glycolysis

Female

Transcription, Genetic

Mice

PPAR alpha - metabolism

Proto-Oncogene Proteins c-akt - metabolism

Transgenes

Fatty Acids - metabolism

Cardiomegaly - metabolism

Hypertrophy

Details

Title: Subtitle: 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
Creators: Adam R Wende - 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
Brian T O'Neill - 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
Heiko Bugger - 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
Christian Riehle - 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
Joseph Tuinei - Program in Molecular Medicine and Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, Utah, USA
Jonathan Buchanan - Program in Molecular Medicine and Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, Utah, USA
Kensuke Tsushima - 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
Li Wang - Program in Molecular Medicine and Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, Utah, USA
Pilar Caro - Program in Molecular Medicine and Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, Utah, USA
Aili Guo - 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
Crystal Sloan - Program in Molecular Medicine and Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, Utah, USA
Bum Jun Kim - Program in Molecular Medicine and Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, Utah, USA
Xiaohui Wang - Program in Molecular Medicine and Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, Utah, USA
Renata O Pereira - 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
Mark A McCrory - Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA
Brenna G Nye - Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA
Gloria A Benavides - Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA
Victor M Darley-Usmar - Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA
Tetsuo Shioi - Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Bart C Weimer - Department of Population Health and Reproduction, University of California, Davis, School of Veterinary Medicine, Davis, California, USA
E Dale Abel - 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
Resource Type: Journal article
Publication Details: Molecular and cellular biology, Vol.35(5), pp.831-846
DOI: 10.1128/MCB.01109-14
PMID: 25535334
PMCID: PMC4323486
NLM abbreviation: Mol Cell Biol
ISSN: 0270-7306
eISSN: 1098-5549
Publisher: United States
Grant note: U01HL70525 / NHLBI NIH HHS K99 HL111322 / NHLBI NIH HHS U01 HL070525 / NHLBI NIH HHS K99R00 HL111322 / NHLBI NIH HHS R00 HL111322 / NHLBI NIH HHS R01 HL070070 / NHLBI NIH HHS T32 HL007576 / NHLBI NIH HHS R01 DK092065 / NIDDK NIH HHS U54 HL112311 / NHLBI NIH HHS R01DK092065 / NIDDK NIH HHS R01HL070070 / NHLBI NIH HHS
Language: English
Date published: 03/2015
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984024540802771

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