Resveratrol Ameliorates Mitophagy Disturbance and Improves Cardiac Pathophysiology of Dystrophin-deficient mdx Mice.
Resveratrol Ameliorates Mitophagy Disturbance and Improves Cardiac Pathophysiology of Dystrophin-deficient mdx Mice.
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DOI：
10.1038/s41598-018-33930-w
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发表时间：
2018-10-22
影响因子：
4.6
通讯作者：
Horio Y
中科院分区：
文献类型：
--
作者：
Kuno A;Hosoda R;Sebori R;Hayashi T;Sakuragi H;Tanabe M;Horio Y
自噬激活改善了mdx小鼠（Duchenne肌营养不良症（DMD）模型）的表型，尽管其潜在机制尚不清楚。我们先前发现，白藜芦醇，一个强大的自噬诱导剂，改善mdx小鼠的心脏病理。自噬可以清除受损的线粒体，这是细胞内活性氧（ROS）的主要来源，尽管没有证据表明营养不良性心肌病中存在线粒体病变。为了阐明白藜芦醇的功能，我们研究了mdx小鼠心脏中线粒体DNA（mtDNA）的缺失、受损线粒体的自噬（线粒体自噬）和ROS积累。在mdx小鼠心脏中发现了低水平的正常mtDNA和含有自噬体的线粒体的异常积累。给mdx小鼠施用白藜芦醇56周改善了心肌病，线粒体DNA缺失量，含白藜芦醇的自噬体数量和ROS水平显着降低。白藜芦醇诱导细胞核FoxO 3a的积累和自噬相关基因的表达，这些基因是FoxOs的靶点。在mdx小鼠中最有效的剂量是0.4 g白藜芦醇/kg食物。总之，白藜芦醇通过促进mdx小鼠心脏的线粒体自噬来改善心肌病。我们认为获得性心肌病是DMD患者心肌病的一个潜在治疗靶点。
Autophagy activation improves the phenotype in mdx mice, a Duchenne muscular dystrophy (DMD) model, although the underlying mechanisms are obscure. We previously found that resveratrol, a strong inducer of autophagy, ameliorates the cardiac pathology of mdx mice. Autophagy could eliminate damaged mitochondria, a major source of intracellular reactive oxygen species (ROS), although there is no evidence for mitochondriopathy in dystrophic cardiomyopathy. To elucidate resveratrol’s function, we investigated the deletion of mitochondrial DNA (mtDNA), autophagy of damaged mitochondria (mitophagy), and ROS accumulation in the mdx mouse heart. Low levels of normal mtDNA and abnormal accumulations of mitochondria-containing autophagosomes were found in the mdx mouse heart. Administering resveratrol to mdx mice for 56 weeks ameliorated the cardiomyopathy, with significant reductions in the amount of mtDNA deletion, the number of mitochondria-containing autophagosomes, and the ROS levels. Resveratrol induced nuclear FoxO3a accumulation and the expression of autophagy-related genes, which are targets of FoxOs. The most effective dose in mdx mice was 0.4 g resveratrol/kg food. In conclusion, resveratrol improved cardiomyopathy by promoting mitophagy in the mdx mouse heart. We propose that acquired mitochondriopathy worsens the pathology of DMD and is a potential therapeutic target for the cardiomyopathy in DMD patients.
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影响因子：
9
作者：
通讯作者：
--
影响因子：
16.6
作者：
Milan, Giulia;Romanello, Vanina;Pescatore, Francesca;Armani, Andrea;Paik, Ji-Hye;Frasson, Laura;Seydel, Anke;Zhao, Jinghui;Abraham, Reimar;Goldberg, Alfred L.;Blaauw, Bert;DePinho, Ronald A.;Sandri, Marco
通讯作者：
Sandri, Marco
影响因子：
4
作者：
Huang, Haojie;Tindall, Donald J.
通讯作者：
Tindall, Donald J.
影响因子：
11.4
作者：
Pena-Llopis, Samuel;Vega-Rubin-de-Celis, Silvia;Schwartz, Jacob C.;Wolff, Nicholas C.;Tran, Tram Anh T.;Zou, Lihua;Xie, Xian-Jin;Corey, David R.;Brugarolas, James
通讯作者：
Brugarolas, James
DOI：
10.1083/jcb.201008167
发表时间：
2011-02-21
期刊：
The Journal of cell biology
影响因子：
--
作者：
Morselli E;Mariño G;Bennetzen MV;Eisenberg T;Megalou E;Schroeder S;Cabrera S;Bénit P;Rustin P;Criollo A;Kepp O;Galluzzi L;Shen S;Malik SA;Maiuri MC;Horio Y;López-Otín C;Andersen JS;Tavernarakis N;Madeo F;Kroemer G
通讯作者：
Kroemer G