Department of Physiology, University of Kentucky, Lexington, Kentucky 40536-0298, USA.
Am J Physiol Cell Physiol. 2012 Jan 1;302(1):C195-202. doi: 10.1152/ajpcell.00217.2011. Epub 2011 Sep 21.
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 μM). 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.
阿霉素是一种常用的化疗药物，会导致接受治疗的癌症患者的骨骼肌减少，并增加线粒体活性氧（ROS）的产生。ROS 通过激活包括半胱天冬酶-3 和泛素蛋白酶体途径在内的蛋白水解系统，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 泛素连接酶和半胱天冬酶-3 的上调。我们通过将分化的 C2C12 肌管暴露于阿霉素（0.2 μM）来检验这一假设。在暴露后 48 小时，阿霉素降低了肌管的宽度，肌球蛋白和肌节肌动蛋白减少了 40-50%。阿霉素暴露后 2 小时，肌管中的细胞溶质氧化剂活性升高。这种氧化剂的增加随后导致 E3 泛素连接酶 atrogin-1/肌肉萎缩 F 盒（MAFbx）和半胱天冬酶-3 的增加。用 SS31（对抗线粒体 ROS）处理肌管可抑制 ROS 敏感的 atrogin-1/MAFbx 的表达，并防止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 作用于刺激肌管萎缩。
