title: Impairments in mitochondrial palmitoyl-CoA respiratory kinetics that precede development of diabetic cardiomyopathy are prevented by resveratrol in ZDF rats.
abstract: Alterations in lipid metabolism within the heart may have a causal role in the establishment of diabetic cardiomyopathy; however, this remains equivocal. Therefore, in the current study we determined cardiac mitochondrial bioenergetics in ZDF rats before overt type 2 diabetes and diabetic cardiomyopathy developed. In addition, we utilized resveratrol, a compound previously shown to improve, prevent or reverse cardiac dysfunction in high-fat-fed rodents, as a tool to potentially recover dysfunctions within mitochondria. Fasting blood glucose and invasive left ventricular haemodynamic analysis confirmed the absence of type 2 diabetes and diabetic cardiomyopathy. However, fibrosis was already increased (P < 0.05) ∼70% in ZDF rats at this early stage in disease progression. Assessments of mitochondrial ADP and pyruvate respiratory kinetics in permeabilized fibres from the left ventricle revealed normal electron transport chain function and content. In contrast, the apparent Km to palmitoyl-CoA (P-CoA) was increased (P < 0.05) ∼60%, which was associated with an accumulation of intracellular triacylgycerol, diacylglycerol and ceramide species. In addition, the capacity for mitochondrial reactive oxygen species emission was increased (P < 0.05) ∼3-fold in ZDF rats. The provision of resveratrol reduced fibrosis, P-CoA respiratory sensitivity, reactive lipid accumulation and mitochondrial reactive oxygen species emission rates. Altogether the current data support the supposition that a chronic dysfunction within mitochondrial lipid-supported bioenergetics contributes to the development of diabetic cardiomyopathy, as this was present before overt diabetes or cardiac dysfunction. In addition, we show that resveratrol supplementation prevents these changes, supporting the belief that resveratrol is a potent therapeutic approach for preventing diabetic cardiomyopathy.
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Ontario, Canada, N1G 2W1.
authors.forename: Marie-Soleil
authors.initials: MS
authors.lastname: Beaudoin
authors.affiliation: School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Ontario, Canada, M3J 1P3.
authors.forename: Christopher G R
authors.initials: CG
authors.lastname: Perry
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Ontario, Canada, N1G 2W1.
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Arkell
authors.affiliation: Department of Physiology, Medical University of Bialystok, 15-222 Bialystok, Poland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Chabowski
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Ontario, Canada, N1G 2W1.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Simpson
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Ontario, Canada, N1G 2W1.
authors.forename: David C
authors.initials: DC
authors.lastname: Wright
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Ontario, Canada, N1G 2W1 ghollowa@uoguelph.ca.
authors.forename: Graham P
authors.initials: GP
authors.lastname: Holloway
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D058065:Diabetic Cardiomyopathies / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D005355:Fibrosis; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007700:Kinetics; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D011924:Rats, Zucker; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D045222:Electron Transport Chain Complex Proteins; D013267:Stilbenes; D010171:Palmitoyl Coenzyme A; D005978:Glutathione; D000077185:Resveratrol; D019803:Glutathione Disulfide