Impairments in mitochondrial palmitoyl‐CoA respiratory kinetics that precede development of diabetic cardiomyopathy are prevented by resveratrol in ZDF rats

Key points Dysfunctional mitochondrial respiration may contribute to the establishment of diabetic cardiomyopathy, but this remains controversial; resveratrol, a polyphenol compound, has been shown to recover heart contractile function in rodent models of high‐fat‐diet‐induced cardiac dysfunction. Therefore, we studied mitochondrial respiratory kinetic function in ZDF rats before overt diabetes and cardiac dysfunction manifested, and determined the efficacy of resveratrol to recover potential derangements in mitochondrial bioenergetics. We show that the electron transport chain functions normally in ZDF rats, as pyruvate and ADP respiratory kinetics were normal. In contrast, in ZDF rats, we show impairments in the sensitivity of mitochondria to lipids (palmitoyl‐CoA) as well as the accumulation of reactive lipids and increased mitochondrial reactive oxygen species (ROS) emission rates. Supplementation with resveratrol improved palmitoyl‐CoA respiratory kinetics and reactive lipid profiles, and normalized mitochondrial ROS emission rates. 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 K m 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.