Contribution Of Impaired Myocardial Insulin Signaling To Mitochondrial Dysfunction And Oxidative Stress In The Heart

Authors

Sihem Boudina, University of Utah School of Medicine
Heiko Bugger, University of Utah School of Medicine
Sandra Sena, University of Utah School of Medicine
Brian T. O'Neill, University of Utah School of Medicine
Vlad G. Zaha, University of Utah School of Medicine
Olesya Ilkun, University of Utah School of Medicine
Jordan J. Wright, University of Utah School of Medicine
Pradip K. Mazumber, University of Utah School of Medicine
Eric Palfreyman, University of Utah School of Medicine
Timothy J. Tidwell, University of Utah School of Medicine
Heather Theobald, University of Utah School of Medicine
Oleh Khalimonchuk, University of Nebraska-LincolnFollow
Benjamin Wayment, University of Utah School of Medicine
Xiaoming Sheng, University of Utah School of Medicine
Kenneth J. Rodnick, Idaho State University
Ryan Centini, Utah State University
Dong Chen, Utah State University
Sheldon E. Litwin, University of Utah School of Medicine
Bart E. Weimer, Utah State University
E. Dale Abel, University of Utah School of MedicineFollow

Document Type

Article

Date of this Version

2009

Citation

Circulation. 2009 March 10; 119(9): 1272–1283.

Comments

Copyright 2009 American Heart Association. Used by permission.

Abstract

Background—Diabetes-associated cardiac dysfunction is associated with mitochondrial dysfunction and oxidative stress, which may contribute to LV dysfunction. The contribution of altered myocardial insulin action, independently 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 substrates glutamate and the fatty acid derivative palmitoyl carnitine (PC) were observed. Mitochondria were also uncoupled when exposed to PC due in part to increased ROS production and oxidative stress. Although proteomic and genomic approaches revealed a reduction in subsets of genes and proteins related to oxidative phosphorylation, no reduction in maximal activities of mitochondrial electron transport chain complexes were found. However, a disproportionate reduction in TCA cycle and FA oxidation proteins in mitochondria, suggest that defects in FA and pyruvate metabolism and TCA flux may explain the mitochondrial dysfunction observed.

Conclusions—Impaired myocardial insulin signaling promotes oxidative stress and mitochondrial uncoupling, which together with reduced TCA and FA oxidative capacity impairs mitochondrial energetics. This study identifies specific contributions of impaired insulin action to mitochondrial dysfunction in the heart.