Abstract
BackgroundCoronary artery disease is a leading cause of morbidity and mortality among patients with diabetes. Previously, we demonstrated that branched-chain amino acids (BCAAs) showed cardioprotective effects against cardiac ischemia/reperfusion (I/R) injury. A recent study suggested that leucine (Leu), a BCAA, is a key amino acid involved in mammalian target of rapamycin (mTOR) activity and mitochondrial function. However, whether Leu has cardioprotective effects on diabetic hearts is unclear. In this study, we examined the preconditioning effect of Leu treatment on high-fat diet (HFD)-induced obese mouse which simulate prediabetic heart.MethodsIn vivo mice models of I/R injury were divided into the following groups: control, mTOR+/−, and high-fat diet (HFD)-induced obese groups. Mice were randomly administered with Leu, the mTOR inhibitor rapamycin (Rap), or Leu with Rap. Isolated rat cardiomyocytes were subjected to simulated I/R injury. Biochemical and mitochondrial functional assays were performed to evaluate the changes in mTOR activity and mitochondrial dynamics caused by Leu treatment.ResultsLeu-treated mice showed a significant reduction in infarct size when compared with the control group (34.8% ± 3.8% vs. 43.1% ± 2.4%, n = 7, p < 0.05), whereas Rap-treated mice did not show the protective effects of Leu. This preconditioning effect of Leu was attenuated in mTOR+/− mice. Additionally, Leu increased the percentage of fused mitochondria and the mitochondrial volume, and decreased the number of mitochondria per cell in isolated cardiomyocytes. In HFD-induced obese mice, Leu treatment significantly reduced infarct size (41.0% ± 1.1% vs. 51.0% ± 1.4%, n = 7, p < 0.05), which was not induced by ischemic preconditioning, and this effect was inhibited by Rap. Furthermore, we observed enhanced mTOR protein expression and mitochondrial fusion with decreased reactive oxygen species production with Leu treatment in HFD-induced obese mice, but not in mTOR+/− mice.ConclusionsLeu treatment improved the damage caused by myocardial I/R injury by promoting mTOR activity and mitochondrial fusion on prediabetic hearts in mice.
Highlights
Coronary artery disease (CAD) is a leading cause of morbidity and mortality among patients with diabetes, which increases the risk of developing CAD by two- to fourfold [1, 2]
We examined the changes in mammalian target of rapamycin (mTOR) activity and mitochondrial dynamics caused by Leu administered during I/R injury of the heart in a high-fat diet (HFD)-induced obese mouse model
Leu reduces infarct size in wild‐type but not in mTOR+/− mice The area at risk was calculated as a percentage of infarct size, and was found to be similar between the groups
Summary
Coronary artery disease (CAD) is a leading cause of morbidity and mortality among patients with diabetes, which increases the risk of developing CAD by two- to fourfold [1, 2]. Both type 1 and type 2 diabetic individuals are prone to developing ischemic heart disease, including acute myocardial infarction (AMI) and post-infarct complications [3]. Coronary artery disease is a leading cause of morbidity and mortality among patients with diabetes. We examined the preconditioning effect of Leu treatment on high-fat diet (HFD)-induced obese mouse which simulate prediabetic heart. Biochemical and mitochondrial functional assays were performed to evaluate the changes in mTOR activity and mitochondrial dynamics caused by Leu treatment
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