Department of Analytical Pathophysiology, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
Department of Physiology and Molecular Sciences, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
Pflugers Arch. 2017 Nov;469(11):1495-1505. doi: 10.1007/s00424-017-2045-4. Epub 2017 Jul 31.
Cisplatin, a platinum-based anti-cancer drug, is one of the most effective broad-spectrum anti-cancer agents used against various cancers. It has been recently suggested that low skeletal muscle mass is predictive of mortality in patients with cancer. Although several molecules produced by the actual tumor itself contribute to skeletal muscle impairment, we recently suggested that the administration of cisplatin could increase levels of muscle RING finger-1 (MuRF1) and atrogin-1, possibly leading to muscle atrophy in the mouse. Exercise is an important factor that induces muscle protein synthesis and muscle hypertrophy by enhancing the positive effects of the Akt/mTOR/p70S6 kinase pathway. In the present study, we therefore investigated the effect of treadmill exercise on cisplatin-induced muscle atrophy. C57BL/6J mice were treated with cisplatin (3 mg/kg, i.p.) or saline for four consecutive days. On day 4, the quadriceps and gastrocnemius muscles were isolated from the mice. The animals in the treadmill exercise groups were forced to run on a motorized treadmill for 20 min once a day for 9 days. In addition to muscle mass, the decrease in myofiber diameter associated with cisplatin administration was significantly restored by treadmill exercise. This exercise also significantly attenuated cisplatin-induced upregulation of MuRF1 and atrogin-1 in quadriceps and gastrocnemius muscle. The decreased Akt, p70S6 kinase, and Foxo3a phosphorylation observed with cisplatin treatment was significantly recovered by treadmill exercise in both the muscles. In the present study, myostatin (Mstn) gene expression, upregulated by cisplatin administration, was also attenuated by treadmill exercise. These findings suggest that treadmill exercise could attenuate cisplatin-induced muscle atrophy, at least partially, and could improve prognosis.
顺铂是一种基于铂的抗癌药物，是对抗各种癌症最有效的广谱抗癌药物之一。最近有人提出，骨骼肌量低与癌症患者的死亡率有关。虽然肿瘤本身产生的几种分子确实会导致骨骼肌受损，但我们最近提出，顺铂的给药可能会增加肌肉环指蛋白 1（MuRF1）和萎缩蛋白 1 的水平，从而导致小鼠的肌肉萎缩。运动是通过增强 Akt/mTOR/p70S6 激酶通路的积极作用来诱导肌肉蛋白合成和肌肉肥大的重要因素。因此，在本研究中，我们研究了跑步机运动对顺铂诱导的肌肉萎缩的影响。C57BL/6J 小鼠用顺铂（3mg/kg，腹腔注射）或生理盐水连续处理 4 天。第 4 天，从小鼠中分离出股四头肌和比目鱼肌。跑步机运动组的动物每天被迫在电动跑步机上跑 20 分钟，共 9 天。除了肌肉质量外，跑步机运动还显著恢复了与顺铂给药相关的肌纤维直径减小。这种运动还显著抑制了顺铂诱导的股四头肌和比目鱼肌中 MuRF1 和萎缩蛋白 1 的上调。顺铂处理导致的 Akt、p70S6 激酶和 Foxo3a 磷酸化减少，通过跑步机运动在这两种肌肉中都得到了显著恢复。在本研究中，顺铂给药上调的肌肉生长抑制素（Mstn）基因表达也被跑步机运动减弱。这些发现表明，跑步机运动至少可以部分减轻顺铂诱导的肌肉萎缩，并改善预后。
