Pharmacological targeting of mitochondrial function and reactive oxygen species production prevents colon 26 cancer-induced cardiorespiratory muscle weakness.
Pharmacological targeting of mitochondrial function and reactive oxygen species production prevents colon 26 cancer-induced cardiorespiratory muscle weakness.
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DOI：
10.18632/oncotarget.27748
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发表时间：
2020-09-22
期刊：
影响因子：
--
通讯作者：
Judge AR
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文献类型：
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作者：
Smuder AJ;Roberts BM;Wiggs MP;Kwon OS;Yoo JK;Christou DD;Fuller DD;Szeto HH;Judge AR
癌症恶病质是一种以严重的心肌和膈肌萎缩为特征的综合征，其增加了癌症患者由于心肺系统衰竭而发病的风险。在这方面，肌肉在很大程度上依赖于线粒体来满足收缩的能量需求，线粒体功能障碍可能导致肌肉无力和疲劳。此外，线粒体是活性氧（ROS）产生的主要来源，其可以刺激肌肉蛋白质降解速率的增加。因此，有人认为线粒体功能障碍可能是导致癌症恶病质病理学的潜在因素。为了确定通过用靶向大肠杆菌的肽SS-31治疗靶向线粒体功能障碍的大肠杆菌是否会预防心肺肌功能障碍，在接种后每天向携带结肠26（C26）腺癌肿瘤的小鼠施用盐水或SS-31（3 mg/kg/天）。与接受SS-31的C26小鼠相比，在心脏和膈肌中，用盐水处理的C26小鼠表现出更大的ROS产生和线粒体解偶联。此外，盐水处理的C26小鼠表现出左心室功能下降，这在用SS-31处理的C26小鼠中得到显著挽救。在膈肌中，与C26、SS-31处理的动物相比，用盐水处理的C26小鼠的肌纤维横截面积显著减少，并且力产生受损。最后，与盐水处理相比，用SS-31处理的C26小鼠的排便缺陷也减弱。这些数据表明，C26肿瘤会导致严重的心脏和呼吸道肌病，而预防线粒体功能障碍足以预防癌症恶病质诱导的心肺功能障碍。
Cancer cachexia is a syndrome characterized by profound cardiac and diaphragm muscle wasting, which increase the risk of morbidity in cancer patients due to failure of the cardiorespiratory system. In this regard, muscle relies greatly on mitochondria to meet energy requirements for contraction and mitochondrial dysfunction can result in muscle weakness and fatigue. In addition, mitochondria are a major source of reactive oxygen species (ROS) production, which can stimulate increased rates of muscle protein degradation. Therefore, it has been suggested that mitochondrial dysfunction may be an underlying factor that contributes to the pathology of cancer cachexia. To determine if pharmacologically targeting mitochondrial dysfunction via treatment with the mitochondria-targeting peptide SS-31 would prevent cardiorespiratory muscle dysfunction, colon 26 (C26) adenocarcinoma tumor-bearing mice were administered either saline or SS-31 daily (3 mg/kg/day) following inoculation. C26 mice treated with saline demonstrated greater ROS production and mitochondrial uncoupling compared to C26 mice receiving SS-31 in both the heart and diaphragm muscle. In addition, saline-treated C26 mice exhibited a decline in left ventricular function which was significantly rescued in C26 mice treated with SS-31. In the diaphragm, muscle fiber cross-sectional area of C26 mice treated with saline was significantly reduced and force production was impaired compared to C26, SS-31-treated animals. Finally, ventilatory deficits were also attenuated in C26 mice treated with SS-31, compared to saline treatment. These data demonstrate that C26 tumors promote severe cardiac and respiratory myopathy, and that prevention of mitochondrial dysfunction is sufficient to preclude cancer cachexia-induced cardiorespiratory dysfunction.