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Contribution of impaired myocardial insulin signaling to mitochondrial dysfunction and oxidative stress in the heart.

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.

SUBMITTER: Boudina S

PROVIDER: S-EPMC2739097 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Contribution of impaired myocardial insulin signaling to mitochondrial dysfunction and oxidative stress in the heart.

Boudina Sihem S Bugger Heiko H Sena Sandra S O'Neill Brian T BT Zaha Vlad G VG Ilkun Olesya O Wright Jordan J JJ Mazumder Pradip K PK Palfreyman Eric E Tidwell Timothy J TJ Theobald Heather H Khalimonchuk Oleh O Wayment Benjamin B Sheng Xiaoming X Rodnick Kenneth J KJ Centini Ryan R Chen Dong D Litwin Sheldon E SE Weimer Bart E BE Abel E Dale ED

Circulation 20090223 9

<h4>Background</h4>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.<h4>Methods and results</h4>In 8-week-old mice with ca ...[more]

PMID: 19237663

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Contribution of impaired myocardial insulin signaling to mitochondrial dysfunction and oxidative stress in the heart.

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Contribution of impaired myocardial insulin signaling to mitochondrial dysfunction and oxidative stress in the heart.

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