Contribution of impaired myocardial insulin signaling to mitochondrial
dysfunction and oxidative stress in the heart.
Authors Boudina S, Bugger H, Sena S, O'Neill BT, Zaha VG, Ilkun O, Wright JJ, Mazumder
PK, Palfreyman E, Tidwell TJ, Theobald H, Khalimonchuk O, Wayment B, Sheng X,
Rodnick KJ, Centini R, Chen D, Litwin SE, Weimer BE, Abel ED
Submitted By E. Dale Abel on 3/17/2009
Status Published
Journal Circulation
Year 2009
Date Published 3/10/2009
Volume : Pages 119(9) : 1272 - 1283
PubMed Reference 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.

Investigators with authorship
E. Dale AbelUniversity of Iowa