Journal article
Contribution of Impaired Myocardial Insulin Signaling to Mitochondrial Dysfunction and Oxidative Stress in the Heart
Circulation (New York, N.Y.), Vol.119(9), pp.1272-1283
2009
DOI: 10.1161/CIRCULATIONAHA.108.792101
PMCID: PMC2739097
PMID: 19237663
Abstract
Background: Diabetes-associated cardiac dysfunction is associated with mitochondrial dysfunction and oxidative stress, which may contribute to left ventricular dysfunction. The contribution of altered myocardial insulin action, independent of associated changes in systemic metabolism, is incompletely understood. The present study tested the hypothesis that perinatal loss of insulin signaling in the heart impairs mitochondrial function.
Methods and results: In 8-week-old mice with cardiomyocyte deletion of insulin receptors (CIRKO), inotropic reserves were reduced, and mitochondria manifested respiratory defects for pyruvate that was associated with proportionate reductions in catalytic subunits of pyruvate dehydrogenase. Progressive age-dependent defects in oxygen consumption and ATP synthesis with the substrate glutamate and the fatty acid derivative palmitoyl-carnitine were observed. Mitochondria also were uncoupled when exposed to palmitoyl-carnitine, in part as a result of increased reactive oxygen species production and oxidative stress. Although proteomic and genomic approaches revealed a reduction in subsets of genes and proteins related to oxidative phosphorylation, no reductions in maximal activities of mitochondrial electron transport chain complexes were found. However, a disproportionate reduction in tricarboxylic acid cycle and fatty acid oxidation proteins in mitochondria suggests that defects in fatty acid and pyruvate metabolism and tricarboxylic acid flux may explain the mitochondrial dysfunction observed.
Conclusions: Impaired myocardial insulin signaling promotes oxidative stress and mitochondrial uncoupling, which, together with reduced tricarboxylic acid and fatty acid oxidative capacity, impairs mitochondrial energetics. This study identifies specific contributions of impaired insulin action to mitochondrial dysfunction in the heart.
Details
- Title: Subtitle
- Contribution of Impaired Myocardial Insulin Signaling to Mitochondrial Dysfunction and Oxidative Stress in the Heart
- Creators
- Sihem BOUDINA - Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, United StatesHeiko BUGGER - Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, United StatesHeather THEOBALD - Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, United StatesOleh KHALIMONCHUK - Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, United StatesBenjamin WAYMENT - Division of Cardiology, University of Utah School of Medicine, Salt Lake City, United StatesXiaoming Sheng - Department of Family and PreventiveMedicine, University of Utah School of Medicine, Salt Lake City, United StatesKenneth J RODNICK - Department of Biological Sciences, Idaho State University, Pocatello, United StatesRyan CENTINI - Center for Integrated BioSystems, Utah State University, Logan, United StatesSheldon E LITWIN - Division of Cardiology, University of Utah School of Medicine, Salt Lake City, United StatesBart E WEIMER - Center for Integrated BioSystems, Utah State University, Logan, United StatesE Dale Abel - Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, United StatesSandra SENA - Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, United StatesBrian T O'NEILL - Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, United StatesVlad G ZAHA - Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, United StatesOlesya ILKUN - Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, United StatesJordan J WRIGHT - Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, United StatesPradip K MAZUMDER - Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, United StatesEric PALFREYMAN - Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, United StatesTimothy J TIDWELL - Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, United States
- Resource Type
- Journal article
- Publication Details
- Circulation (New York, N.Y.), Vol.119(9), pp.1272-1283
- DOI
- 10.1161/CIRCULATIONAHA.108.792101
- PMID
- 19237663
- PMCID
- PMC2739097
- NLM abbreviation
- Circulation
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Publisher
- Lippincott Williams & Wilkins; Hagerstown, MD
- Language
- English
- Date published
- 2009
- 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
- 9984024535802771
Metrics
14 Record Views