Doxorubicin acts via mitochondrial ROS to stimulate catabolism in C2C12 myotubes
Doxorubicin acts via mitochondrial ROS to stimulate catabolism in C2C12 myotubes
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DOI：
10.1152/ajpcell.00217.2011
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发表时间：
2012-01-01
影响因子：
5.5
通讯作者：
Reid, Michael B.
中科院分区：
文献类型：
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作者：
Gilliam, Laura A. A.;Moylan, Jennifer S.;Reid, Michael B.
乔利亚姆LA，莫伊兰JS，帕特森EW，史密斯JD，威尔逊AS，拉巴尼Z，里德MB。阿霉素通过线粒体ROS刺激C2C12肌管分解代谢。Am J Physiol Cell Physiol 302：C195-C202,2012。2011年9月21日首次出版；DOI：10.1152/ajpcell.00217.2011。-阿霉素，一种常用的处方化疗药物，会导致正在接受治疗的癌症患者骨骼肌萎缩，并增加线粒体活性氧(ROS)的产生。ROS通过激活包括caspase-3和泛素-蛋白酶体途径在内的蛋白分解系统来刺激肌肉中的蛋白质降解。我们假设阿霉素通过ROS引起骨骼肌分解代谢，导致E3泛素连接酶和caspase-3上调。我们通过将分化的C2C12肌管暴露于阿霉素(0.2mM)来验证这一假设。阿霉素在暴露后48小时减少了肌管宽度，同时肌球蛋白和肌节肌动蛋白减少了40%-50%。阿霉素作用2小时后，肌管胞浆氧化剂活性升高。氧化剂的增加紧随其后的是E3泛素连接酶-1/肌肉萎缩F-box(MAFbx)和caspase-3的增加。SS31(与线粒体ROS相反)处理肌管可抑制ROS敏感的阿托金-1/MAFbx的表达，并保护其免受阿霉素刺激的分解代谢。这些发现表明阿霉素通过线粒体ROS刺激肌管萎缩。
Gilliam LA, Moylan JS, Patterson EW, Smith JD, Wilson AS, Rabbani Z, Reid MB. Doxorubicin acts via mitochondrial ROS to stimulate catabolism in C2C12 myotubes. Am J Physiol Cell Physiol 302: C195-C202, 2012. First published September 21, 2011; doi:10.1152/ajpcell.00217.2011.-Doxorubicin, a commonly prescribed chemotherapeutic agent, causes skeletal muscle wasting in cancer patients undergoing treatment and increases mitochondrial reactive oxygen species (ROS) production. ROS stimulate protein degradation in muscle by activating proteolytic systems that include caspase-3 and the ubiquitin-proteasome pathway. We hypothesized that doxorubicin causes skeletal muscle catabolism through ROS, causing upregulation of E3 ubiquitin ligases and caspase-3. We tested this hypothesis by exposing differentiated C2C12 myotubes to doxorubicin (0.2 mu M). Doxorubicin decreased myotube width 48 h following exposure, along with a 40-50% reduction in myosin and sarcomeric actin. Cytosolic oxidant activity was elevated in myotubes 2 h following doxorubicin exposure. This increase in oxidants was followed by an increase in the E3 ubiquitin ligase atrogin-1/muscle atrophy F-box (MAFbx) and caspase-3. Treating myotubes with SS31 (opposes mitochondrial ROS) inhibited expression of ROS-sensitive atrogin-1/MAFbx and protected against doxorubicin-stimulated catabolism. These findings suggest doxorubicin acts via mitochondrial ROS to stimulate myotube atrophy.