Physical exercise prior and during treatment reduces sub-chronic doxorubicin-induced mitochondrial toxicity and oxidative stress
Physical exercise prior and during treatment reduces sub-chronic doxorubicin-induced mitochondrial toxicity and oxidative stress
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DOI：
10.1016/j.mito.2014.10.008
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发表时间：
2015-01-01
期刊：
影响因子：
4.4
通讯作者：
Ascensao, Antonio
中科院分区：
文献类型：
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作者：
Marques-Aleixo, Ines;La Santos-Alves, Este;Ascensao, Antonio
阿霉素 (DOX) 是一种抗癌药物，其临床使用会导致累积的、剂量依赖性的心脏毒性。我们之前已经证明，在 DOX 治疗之前进行运动可以减少由此产生的心脏（线粒体）毒性。我们试图确定两种不同的慢性运动模型（耐力跑步机训练 - TM 和自愿自由轮活动 - FW）在 DOX 治疗之前和期间使用时对心脏线粒体毒性的影响。将雄性年轻 Sprague Dawley 大鼠分为六组（每组 n = 6 只）：SAL + SED（盐水静坐）、SAL + TM（12 周 TM）、SAL + FW（12 周 FW）、DOX + SED（7 周慢性 DOX 治疗，每周 2 mg/kg）、DOX + TM 和 DOX + FW。 DOX 给药在运动方案开始后 5 周开始。评估了心脏线粒体超微结构改变、线粒体功能（耗氧量和膜电位）、氧化磷酸化 (OXPHOS) 蛋白的半定量及其凝胶内活性，以及参与线粒体氧化应激的蛋白（SIRT3、p66shc 和 UCP2）、生物合成（PGC1 α 和 TFAM）、乙酰化和氧化损伤标记物（羰基、MDA、-SH、乌头酸酶、Mn-SOD 活性）。 DOX 治疗导致超微结构和功能改变，并减少 OXPHOS。此外，DOX 降低了复合物 I 活性和含量、线粒体生物合成 (TFAM)、乙酰化和氧化应激增加。TM 和 FW 阻止 DOX 诱导的 OXPHOS 改变、氧化应激增加、复合物 V 活性和复合物 I 活性和含量的降低。仅 TM 可以预防 DOX 诱导的 TFAM 和 SIRT3 含量降低。在亚慢性 DOX 治疗之前和过程中进行的两种慢性体育锻炼模型都转化为改善的线粒体生物能健身，这可能部分来自预防线粒体氧化应激和损伤 (C) 2014 Elsevier BM 和线粒体研究协会保留所有权利。
Doxorubicin (DOX) is an anti-cancer agent whose clinical usage results in a cumulative and dose-dependent cardiotoxicity. We have previously shown that exercise performed prior to DOX treatment reduces the resulting cardiac(mito) toxicity. We sought to determine the effects on cardiac mitochondrial toxicity of two distinct chronic exercise models (endurance treadmill training-TM and voluntary free-wheel activity-FW) when used prior and during DOX treatment.Male-young Sprague Dawley rats were divided into six groups (n = 6 per group): SAL + SED (saline sedentary), SAL + TM (12-weeks TM), SAL + FW (12-weeks FW), DOX + SED (7-weeks of chronic DOX treatment 2 mg/kg per week), DOX + TM and DOX + FW. DOX administration started 5 weeks after the beginning of the exercise protocol. Heart mitochondrial ultrastructural alterations, mitochondrial function (oxygen consumption and membrane potential), semi-quantification of oxidative phosphorylation (OXPHOS) proteins and their in-gel activity, as well as proteins involved in mitochondrial oxidative stress (SIRT3, p66shc and UCP2), biogenesis (PGC1 alpha and TFAM), acetylation and markers for oxidative damage (carbonyl groups, MDA, - SH, aconitase, Mn-SOD activity) were evaluated. DOX treatment resulted in ultrastructural and functional alterations and decreased OXPHOS. Moreover, DOX decreased complex I activity and content, mitochondria( biogenesis (TFAM), increased acetylation and oxidative stress. TM and FW prevented DOX-induced alteration in OXPHOS, the increase in oxidative stress, the decrease in complex V activity and in complex I activity and content. DOX-induced decreases in TFAM and SIRT3 content were prevented by TM only.Both chronic models of physical exercise performed before and during the course of sub-chronic DOX treatment translated into an improved mitochondrial bioenergetic fitness, which may result in part from the prevention of mitochondrial oxidative stress and damage. (C) 2014 Elsevier BM. and Mitochondria Research Society. All rights reserved.