Elsevier

Molecular Metabolism

Volume 39, September 2020, 101012
Molecular Metabolism

Original Article
Exercise training reverses cancer-induced oxidative stress and decrease in muscle COPS2/TRIP15/ALIEN

https://doi.org/10.1016/j.molmet.2020.101012Get rights and content
Under a Creative Commons license
open access

Highlights

  • Exercise training prolongs lifespan, reduces oxidative stress, and improves skeletal muscle function in tumor-bearing rats.

  • Muscle COP9 signalosome complex subunit 2 (COPS2) protein is downregulated in cancer cachexia.

  • Exercise training restores COPS2 protein expression to control levels.

  • Cancer-conditioned media decreased F-actin expression in myotubes, which is partially restored by COPS2 knockdown.

  • COPS2 overexpression decreases DR4 activity and COPS2 knockdown inhibits cancer-conditioned media effects on DR4 activity.

Abstract

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.

Keywords

Cancer cachexia
Muscle wasting
Atrophy
Endurance exercise
Response elements

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