title: 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.
  
  
  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.
authors.affiliation: University of Utah School of Medicine, Salt Lake City, 84112, USA.
authors.forename: Sihem
authors.initials: S
authors.lastname: Boudina
authors.forename: Heiko
authors.initials: H
authors.lastname: Bugger
authors.forename: Sandra
authors.initials: S
authors.lastname: Sena
authors.forename: Brian T
authors.initials: BT
authors.lastname: O'Neill
authors.forename: Vlad G
authors.initials: VG
authors.lastname: Zaha
authors.forename: Olesya
authors.initials: O
authors.lastname: Ilkun
authors.forename: Jordan J
authors.initials: JJ
authors.lastname: Wright
authors.forename: Pradip K
authors.initials: PK
authors.lastname: Mazumder
authors.forename: Eric
authors.initials: E
authors.lastname: Palfreyman
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Tidwell
authors.forename: Heather
authors.initials: H
authors.lastname: Theobald
authors.forename: Oleh
authors.initials: O
authors.lastname: Khalimonchuk
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wayment
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Sheng
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Rodnick
authors.forename: Ryan
authors.initials: R
authors.lastname: Centini
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.forename: Sheldon E
authors.initials: SE
authors.lastname: Litwin
authors.forename: Bart E
authors.initials: BE
authors.lastname: Weimer
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D004452:Echocardiography; D042967:Electron Transport Complex I / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D028361:Mitochondrial Diseases / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D025261:Mitochondrial Proton-Translocating ATPases; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology*; D010101:Oxygen Consumption / Q000502:physiology; D010641:Phenotype; D040901:Proteomics; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D011972:Receptor, Insulin; D000251:Adenosine Triphosphatases; D025261:Mitochondrial Proton-Translocating ATPases; D042967:Electron Transport Complex I; C020439:oligomycin sensitivity-conferring protein