Beaudoin 2014 J Physiol
|Beaudoin MS, Perry CC, Arkell A, Chabowski A, Simpson JA, Wright DC, Holloway GP (2014) In the ZDF rat, impairments in mitochondrial palmitoyl-CoA respiratory kinetics that precede the development of diabetic cardiomyopathy are prevented by resveratrol supplementation. J Physiol 592:2519-33.|
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 potential recover dysfunctions within mitochondria. Fasting blood glucose and invasive left ventricular hemodynamic 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 ROS emission was increased (P<0.05) ~3-fold in ZDF rats. The provision of resveratrol recovered fibrosis, P-CoA respiratory sensitivity, reactive lipid accumulation and mitochondrial reactive oxygen species emission rates. Altogether the current data supports 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 resveratrol supplementation prevents these changes, supporting the belief that resveratrol is a potent therapeutic approach for preventing diabetic cardiomyopathy.
• Keywords: Diabetic cardiomyopathy, Mitochondria, Type 2 diabetes mellitus, Heart, Fatty acid oxidation, ZDF rat, Blebbistatin
• O2k-Network Lab: CA Guelph Holloway GP
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Diabetes
Organism: Rat Tissue;cell: Heart Preparation: Permeabilized tissue
Regulation: ADP, Substrate, Fatty acid Coupling state: LEAK, OXPHOS Pathway: N HRR: Oxygraph-2k