Physical exercise positively modulates DOX-induced hepatic oxidative stress, mitochondrial dysfunction and quality control signaling
Physical exercise positively modulates DOX-induced hepatic oxidative stress, mitochondrial dysfunction and quality control signaling
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DOI：
10.1016/j.mito.2019.05.008
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发表时间：
2019-07-01
期刊：
影响因子：
4.4
通讯作者：
Antonio, Ascensao
中科院分区：
文献类型：
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作者：
Estela, Santos-Alves;David, Rizo-Roca;Antonio, Ascensao
多柔比星（DOX）是一种广泛应用的高效抗肿瘤药物，其主要限制因素是心脏毒性，但包括肝脏在内的其他组织也会受到影响。运动对DOX副作用的影响已经在心脏和大脑中进行了研究，并取得了成功的结果。然而，这种非药物策略的益处尚未在肝脏中得到广泛的检查。为探讨运动对阿霉素（DOX）肝损伤的影响，采用线粒体模型，将24只雄性大鼠随机分为4组：SED + SAL组（生理盐水组）、SED + DOX组（DOX组）、ET + DOX组（DOX组）和VPA + DOX组（DOX组）。获得分离的肝线粒体用于评价其呼吸活性和跨膜电位终点。测量氧化损伤的分子标志物（羰基、MDA、顺乌头酸酶、MnSOD）、线粒体动力学（PGC-1 α、TFAM、OPA 1、DRP 1、MFN 1）和自动（线粒体）吞噬信号传导（p62、LC 3、Beclinl、Bcl-2、PINK、Parkin）。透射电镜观察线粒体形态学改变，与SED + SAL组相比，SED + DOX组呼吸功能受损。DOX处理后SOD和顺乌头酸酶活性降低，MDA含量增加，PGC-1 α、TFAM、OPA 1和MFN 1表达减少，DRP 1和LC 3 II/LC 3 I比值增加。然而，这些改变在ET + DOX组中被逆转或减轻。半定量和定性分析表明，SED + DOX动物的肝线粒体更圆，密度更低，而运动动物显示出逆转这种表型和增加线粒体密度的趋势。线粒体功能障碍和改变的线粒体动力学向分裂，从而有助于增加肝脏对DOX给药的抗性。
Doxorubicin (DOX), a widely used and efficient antineoplastic agent, is mainly limited by cardiotoxicity, although other tissues including liver are also affected. The effects of exercise to cope with DOX side-effects has already been studied in the heart and brain, demonstrating successful results. However, the benefits of this non pharmacological strategy have not been so extensively checked in the liver. We here aimed to ascertain whether exercise could mitigate DOX-induced liver harmful effects using mitochondria as a model for evaluating toxicity.Twenty-four male rats were divided into four groups: SED + SAL (sedentary with saline administration), SED + DOX (sedentary with DOX administration), ET + DOX (endurance-trained with DOX administration) and VPA + DOX (voluntary physical activity with DOX administration). Isolated liver mitochondria were obtained for evaluation of their respiratory activity and transmembrane electrical potential endpoints. Molecular markers of oxidative damage (carbonyls, MDA, aconitase, MnSOD), mitochondrial dynamics (PGC-1 alpha, TFAM, OPA1, DRP1, MFN1) and auto(mito)phagy signaling (p62, LC3, Beclinl, Bcl-2, PINK, Parkin) were measured. Transmission electron microscopy evaluation was used to analyze mitochondrial morphological alterations.When compared to SED + SAL, respiratory function of SED + DOX was compromised. Decreased SOD and aconitase activities and increased MDA content, decreases in PGC-1 alpha, TFAM, OPA1 and MFN1 expressions, and increases in DRP1 and LC3II/LC3I ratio were also observed after DOX administration. However, these alterations were reverted or mitigated in the ET + DOX group. Semi-quantitative and qualitative analyses from microphotographs showed that liver mitochondria of SED + DOX animals were more circular and had lower density, whereas the animals with exercise showed a tendency to revert this phenotype and increase the mitochondrial density.Taken together, our results suggest that physical exercise, particularly ET, positively reversed the deleterious effects caused by DOX administration, such as oxidative damage, mitochondrial dysfunction, and altered mitochondrial dynamics toward fission, thus contributing to increase liver resistance against DOX administration.