School of Physical Education and Sport, University of Sao Paulo, Sao Paulo, Brazil; Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
School of Physical Education and Sport, University of Sao Paulo, Sao Paulo, Brazil; Instituto do Cancer do Estado de Sao Paulo ICESP, Hospital das Clinicas HC FMUSP, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil.
Mol Metab. 2020 Sep;39:101012. doi: 10.1016/j.molmet.2020.101012. Epub 2020 May 11.
We tested the hypothesis that exercise training would attenuate metabolic impairment in a model of severe cancer cachexia.
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.
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.
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.
我们检验了运动训练可减轻严重癌性恶病质模型代谢损伤这一假说。
我们使用多种体内和体外方法，探究了运动训练对荷瘤大鼠产生有益效果的潜在机制。
运动训练提高了荷瘤大鼠的跑步能力、延长了其寿命、减轻了氧化应激、使肌肉质量和收缩功能正常化。一项无偏蛋白组学筛选发现，COP9 信号osome 复合物亚基 2（COPS2）是癌性恶病质早期骨骼肌中下调最明显的蛋白之一。运动训练使荷瘤大鼠的骨骼肌 COPS2 蛋白表达恢复正常。与年龄匹配的对照受试者相比，耐力较低的肺癌患者的骨骼肌 COPS2 蛋白表达较低。为了检验 COPS2 蛋白水平降低是否会加重或成为保护肌管免受癌症影响的内在代偿机制，我们在体外使用原代肌管进行了实验。人肌管中的 COPS2 敲低会影响多种细胞通路，包括肌动蛋白细胞骨架的调节。将癌细胞条件培养基孵育于鼠肌管中会降低 F-肌动蛋白表达，而 COPS2 敲低可部分恢复该表达。重复序列 4（DR4）反应元件已被证明可正向调节基因表达。COPS2 过表达可降低鼠成肌细胞中的 DR4 活性，而 COPS2 敲低可抑制癌细胞条件培养基对 DR4 活性的影响。
这些研究表明，运动训练可能是一种对抗癌性恶病质的重要辅助治疗方法，并揭示了涉及 COPS2 的新机制，以调节癌性恶病质中的肌管稳态。
