姜黄素通过 NADPH 氧化酶依赖的氧化还原信号和线粒体保护减轻 C2C12 成肌细胞和小鼠骨骼肌的热诱导损伤。
Curcumin Ameliorates Heat-Induced Injury through NADPH Oxidase-Dependent Redox Signaling and Mitochondrial Preservation in C2C12 Myoblasts and Mouse Skeletal Muscle.
机构信息
Consortium for Health and Military Performance, Department of Military and Emergency Medicine, F Edward Hébert School of Medicine, Uniformed Services University, Bethesda, MD, USA.
Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
出版信息
J Nutr. 2020 Sep 1;150(9):2257-2267. doi: 10.1093/jn/nxaa201.
BACKGROUND
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and the mitochondrial electron transport chain are the primary sources of reactive oxygen species (ROS). Previous studies have shown that severe heat exposure damages mitochondria and causes excessive mitochondrial ROS production that contributes to the pathogenesis of heat-related illnesses.
OBJECTIVES
We tested whether the antioxidant curcumin could protect against heat-induced mitochondrial dysfunction and skeletal muscle injury, and characterized the possible mechanism.
METHODS
Mouse C2C12 myoblasts and rat flexor digitorum brevis (FDB) myofibers were treated with 5 μM curcumin; adult male C57BL/6J mice received daily curcumin (15, 50, or 100 mg/kg body weight) by gavage for 10 consecutive days. We compared ROS levels and mitochondrial morphology and function between treatment and nontreatment groups under unheated or heat conditions, and investigated the upstream mechanism and the downstream effect of curcumin-regulated ROS production.
RESULTS
In C2C12 myoblasts, curcumin prevented heat-induced mitochondrial fragmentation, ROS overproduction, and apoptosis (all P < 0.05). Curcumin treatment for 2 and 4 h at 37°C induced increases in ROS levels by 42% and 59% (dihydroethidium-derived fluorescence), accompanied by increases in NADPH oxidase protein expression by 24% and 32%, respectively (all P < 0.01). In curcumin-treated cells, chemical inhibition and genetic knockdown of NADPH oxidase restored ROS to levels similar to those of controls, indicating NADPH oxidase mediates curcumin-stimulated ROS production. Moreover, curcumin induced ROS-dependent shifting of the mitochondrial fission-fusion balance toward fusion, and increases in mitochondrial mass by 143% and membrane potential by 30% (both P < 0.01). In rat FDB myofibers and mouse gastrocnemius muscles, curcumin preserved mitochondrial morphology and function during heat stress, and prevented heat-induced mitochondrial ROS overproduction and tissue injury (all P < 0.05).
CONCLUSIONS
Curcumin regulates ROS hormesis favoring mitochondrial fusion/elongation, biogenesis, and improved function in rodent skeletal muscle. Curcumin may be an effective therapeutic target for heat-related illness and other mitochondrial diseases.
背景
烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶和线粒体电子传递链是活性氧（ROS）的主要来源。先前的研究表明，严重的热暴露会损害线粒体并导致过多的线粒体 ROS 产生，从而导致与热相关疾病的发病机制。
目的
我们测试了抗氧化剂姜黄素是否可以防止热诱导的线粒体功能障碍和骨骼肌损伤，并对可能的机制进行了描述。
方法
用 5 μM 姜黄素处理小鼠 C2C12 成肌细胞和大鼠屈趾肌纤维（FDB）肌纤维；成年雄性 C57BL/6J 小鼠连续 10 天每天通过灌胃接受姜黄素（15、50 或 100mg/kg 体重）。我们比较了加热和未加热条件下治疗组和未治疗组之间的 ROS 水平、线粒体形态和功能，并研究了姜黄素调节 ROS 产生的上游机制和下游效应。
结果
在 C2C12 成肌细胞中，姜黄素可防止热诱导的线粒体碎片化、ROS 过度产生和凋亡（均 P < 0.05）。在 37°C 下处理 2 和 4 小时后，姜黄素分别使 ROS 水平增加 42%和 59%（二氢乙啶衍生荧光），同时 NADPH 氧化酶蛋白表达分别增加 24%和 32%（均 P < 0.01）。在姜黄素处理的细胞中，NADPH 氧化酶的化学抑制和基因敲低使 ROS 恢复到与对照组相似的水平，表明 NADPH 氧化酶介导姜黄素刺激的 ROS 产生。此外，姜黄素诱导 ROS 依赖性的线粒体分裂-融合平衡向融合转变，并使线粒体质量增加 143%，膜电位增加 30%（均 P < 0.01）。在大鼠 FDB 肌纤维和小鼠比目鱼肌中，姜黄素在热应激期间保持线粒体形态和功能，防止热诱导的线粒体 ROS 过度产生和组织损伤（均 P < 0.05）。
结论
姜黄素调节 ROS 激素作用，有利于线粒体融合/伸长、生物发生和改善啮齿动物骨骼肌功能。姜黄素可能是与热相关疾病和其他线粒体疾病的有效治疗靶点。
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