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(Circulation. 2009;119:1272-1283.)
© 2009 American Heart Association, Inc.

Molecular Cardiology

Contribution of Impaired Myocardial Insulin Signaling to Mitochondrial Dysfunction and Oxidative Stress in the Heart

Sihem Boudina, PhD; Heiko Bugger, MD, PhD; Sandra Sena, PhD; Brian T. O'Neill, MD, PhD; Vlad G. Zaha, MD, PhD; Olesya Ilkun, MS; Jordan J. Wright, BS; Pradip K. Mazumder, DVM, PhD; Eric Palfreyman, MD; Timothy J. Tidwell; Heather Theobald, BS; Oleh Khalimonchuk, PhD; Benjamin Wayment, BS; Xiaoming Sheng, PhD; Kenneth J. Rodnick, PhD; Ryan Centini, BS; Dong Chen, PhD; Sheldon E. Litwin, MD; Bart E. Weimer, PhD; E. Dale Abel, MBBS, DPhil

From the Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine (S.B., H.B., S.S., B.T.O., V.G.Z., O.I., J.J.W., P.K.M., E.P., T.J.T., H.T., E.D.A.), Department of Biochemistry (O.K., E.D.A.), Division of Cardiology (B.W., S.E.L.), and Department of Family and Preventive Medicine (X.S.), University of Utah School of Medicine, Salt Lake City; Department of Biological Sciences, Idaho State University, Pocatello (K.J.R.); and Center for Integrated BioSystems, Utah State University, Logan (R.C., D.C., B.E.W.).

Correspondence to E. Dale Abel, Division of Endocrinology, Metabolism and Diabetes, Program in Molecular Medicine, 15 N 2030 E Bldg No. 533, Room 3110B, Salt Lake City, Utah 84112. E-mail dale.abel{at}hmbg.utah.edu

Received September 20, 2007; accepted January 6, 2009.

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.

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