在心肌缺血/再灌注损伤小鼠模型中，亮氨酸通过增强mTOR活性和线粒体融合发挥心脏保护作用。
Leucine imparts cardioprotective effects by enhancing mTOR activity and mitochondrial fusion in a myocardial ischemia/reperfusion injury murine model.
作者信息
Morio Atsushi, Tsutsumi Rie, Satomi Shiho, Kondo Takashi, Miyoshi Hirotsugu, Kato Takahiro, Kuroda Masashi, Kitamura Tadahiro, Hara Kenta, Saeki Noboru, Sakaue Hiroshi, Tsutsumi Yasuo M
机构信息
Department of Anesthesiology and Critical Care, Hiroshima University, 1-2-3 Kasumi, Minami, Hiroshima, 734-8551, Japan.
Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.
出版信息
Diabetol Metab Syndr. 2021 Nov 20;13(1):139. doi: 10.1186/s13098-021-00755-z.
BACKGROUND
Coronary 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.
METHODS
In 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.
RESULTS
Leu-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.
CONCLUSIONS
Leu treatment improved the damage caused by myocardial I/R injury by promoting mTOR activity and mitochondrial fusion on prediabetic hearts in mice.
背景
冠状动脉疾病是糖尿病患者发病和死亡的主要原因。此前，我们证明支链氨基酸（BCAAs）对心脏缺血/再灌注（I/R）损伤具有心脏保护作用。最近的一项研究表明，亮氨酸（Leu）作为一种BCAA，是参与雷帕霉素靶蛋白（mTOR）活性和线粒体功能的关键氨基酸。然而，Leu对糖尿病心脏是否具有心脏保护作用尚不清楚。在本研究中，我们检测了Leu处理对模拟糖尿病前期心脏的高脂饮食（HFD）诱导的肥胖小鼠的预处理作用。
方法
将I/R损伤的体内小鼠模型分为以下几组：对照组、mTOR组和HFD诱导的肥胖组。小鼠被随机给予Leu、mTOR抑制剂雷帕霉素（Rap）或Leu与Rap联合使用。分离的大鼠心肌细胞接受模拟I/R损伤。进行生化和线粒体功能测定以评估Leu处理引起的mTOR活性和线粒体动力学变化。
结果
与对照组相比，Leu处理的小鼠梗死面积显著减小（34.8%±3.8%对43.1%±2.4%，n = 7，p < 0.05），而Rap处理的小鼠未显示出Leu的保护作用。Leu的这种预处理作用在mTOR小鼠中减弱。此外，Leu增加了分离心肌细胞中融合线粒体的百分比和线粒体体积，并减少了每个细胞中线粒体的数量。在HFD诱导的肥胖小鼠中，Leu处理显著减小了梗死面积（41.0%±1.1%对51.0%±1.4%，n = 7，p < 0.05），这不是由缺血预处理诱导的，且该作用被Rap抑制。此外，我们观察到在HFD诱导的肥胖小鼠中，Leu处理增强了mTOR蛋白表达和线粒体融合，同时活性氧产生减少，但在mTOR小鼠中未观察到。
结论
Leu处理通过促进小鼠糖尿病前期心脏的mTOR活性和线粒体融合，改善了心肌I/R损伤造成的损害。
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