Skeletal muscle atrophy and dysfunction in breast cancer patients: role for chemotherapy-derived oxidant stress
Skeletal muscle atrophy and dysfunction in breast cancer patients: role for chemotherapy-derived oxidant stress
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DOI：
10.1152/ajpcell.00002.2018
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发表时间：
2018-11-01
影响因子：
5.5
通讯作者：
Toth, Michael J.
中科院分区：
文献类型：
--
作者：
Guigni, Blas A.;Callahan, Damien M.;Toth, Michael J.
乳腺癌及其治疗对骨骼肌的影响尚不清楚。为了解决这个问题，我们评估了13名被诊断患有乳腺癌并在肿瘤切除后接受辅助化疗的妇女和12名未患病对照者的骨骼肌结构和蛋白质表达。乳腺癌患者单根肌纤维横截面积减少，肌上皮下和肌纤维间线粒体含量降低。乳腺癌患者常用的药物（多柔比星和紫杉醇）导致C2C12小鼠肌管细胞培养物中肌球蛋白表达降低、线粒体损失和活性氧（ROS）产生增加，支持化疗药物在萎缩和线粒体表型中的作用。此外，用线粒体靶向抗氧化剂MitoQ同时治疗肌管可以防止化疗诱导的肌球蛋白消耗、线粒体损失和ROS产生。在患者中，线粒体含量和大小的减少以及线粒体过氧化物酶过氧化物酶3的表达和氧化增加与肌纤维横截面积的减少有关。我们的研究结果表明，化疗药物可能会对患者的骨骼肌产生不利影响，这些影响可能是通过这些药物对线粒体含量和/或ROS产生的影响来驱动的。
How breast cancer and its treatments affect skeletal muscle is not well defined. To address this question, we assessed skeletal muscle structure and protein expression in 13 women who were diagnosed with breast cancer and receiving adjuvant chemotherapy following tumor resection and 12 nondiseased controls. Breast cancer patients showed reduced single-muscle fiber cross-sectional area and fractional content of subsarcolemmal and intermyofibrillar mitochondria. Drugs commonly used in breast cancer patients (doxorubicin and paclitaxel) caused reductions in myosin expression, mitochondrial loss, and increased reactive oxygen species (ROS) production in C2C12 murine myotube cell cultures, supporting a role for chemotherapeutics in the atrophic and mitochondrial phenotypes. Additionally, concurrent treatment of myotubes with the mitochondrial-targeted antioxidant MitoQ prevented chemotherapy-induced myosin depletion, mitochondrial loss, and ROS production. In patients, reduced mitochondrial content and size and increased expression and oxidation of peroxiredoxin 3, a mitochondrial peroxidase, were associated with reduced muscle fiber cross-sectional area. Our results suggest that chemotherapeutics may adversely affect skeletal muscle in patients and that these effects may be driven through effects of these drugs on mitochondrial content and/or ROS production.