Objective

We tested the hypothesis that exercise training would attenuate metabolic impairment in a model of severe cancer cachexia.

Methods

We used multiple in vivo and in vitro methods to explore the mechanisms underlying the beneficial effects induced by exercise training in tumor-bearing rats.

Results

Exercise training improved running capacity, prolonged lifespan, reduced oxidative stress, and normalized muscle mass and contractile function in tumor-bearing rats. An unbiased proteomic screening revealed COP9 signalosome complex subunit 2 (COPS2) as one of the most downregulated proteins in skeletal muscle at the early stage of cancer cachexia. Exercise training normalized muscle COPS2 protein expression in tumor-bearing rats and mice. Lung cancer patients with low endurance capacity had low muscle COPS2 protein expression as compared to age-matched control subjects. To test whether decrease in COPS2 protein levels could aggravate or be an intrinsic compensatory mechanism to protect myotubes from cancer effects, we performed experiments in vitro using primary myotubes. COPS2 knockdown in human myotubes affected multiple cellular pathways, including regulation of actin cytoskeleton. Incubation of cancer-conditioned media in mouse myotubes decreased F-actin expression, which was partially restored by COPS2 knockdown. Direct repeat 4 (DR4) response elements have been shown to positively regulate gene expression. COPS2 overexpression decreased the DR4 activity in mouse myoblasts, and COPS2 knockdown inhibited the effects of cancer-conditioned media on DR4 activity.

Conclusions

These studies demonstrated that exercise training may be an important adjuvant therapy to counteract cancer cachexia and uncovered novel mechanisms involving COPS2 to regulate myotube homeostasis in cancer cachexia.

中文翻译：

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运动训练可逆转癌症引起的氧化应激并减少肌肉 COPS2/TRIP15/ALIEN。

 客观的

我们在严重癌症恶病质模型中测试了运动训练可以减轻代谢损伤的假设。

 方法

我们使用多种体内和体外方法来探索运动训练对荷瘤大鼠产生有益作用的机制。

 结果

运动训练提高了荷瘤大鼠的跑步能力，延长了寿命，减少了氧化应激，并使肌肉质量和收缩功能正常化。一项公正的蛋白质组学筛查显示，COP9 信号体复合体亚基 2 (COPS2) 是癌症恶病质早期骨骼肌中下调最明显的蛋白质之一。运动训练使荷瘤大鼠和小鼠的肌肉 COPS2 蛋白表达正常化。与年龄匹配的对照受试者相比，耐力能力低的肺癌患者肌肉 COPS2 蛋白表达较低。为了测试 COPS2 蛋白水平的降低是否会加剧或成为保护肌管免受癌症影响的内在补偿机制，我们使用原代肌管进行了体外实验。人类肌管中 COPS2 的敲低影响了多种细胞途径，包括肌动蛋白细胞骨架的调节。在小鼠肌管中孵育癌症条件培养基会降低 F-肌动蛋白的表达，而 COPS2 敲低可部分恢复这种表达。直接重复 4 (DR4) 反应元件已被证明可以正向调节基因表达。 COPS2 过表达降低了小鼠成肌细胞中的 DR4 活性，而 COPS2 敲低则抑制了癌症条件培养基对 DR4 活性的影响。

 结论

这些研究表明，运动训练可能是对抗癌症恶病质的重要辅助疗法，并揭示了涉及 COPS2 调节癌症恶病质肌管稳态的新机制。