1. Exercise training reverses cancer-induced oxidative stress and decrease in muscle COPS2/TRIP15/ALIEN.
- Author
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Alves CRR, Neves WD, de Almeida NR, Eichelberger EJ, Jannig PR, Voltarelli VA, Tobias GC, Bechara LRG, de Paula Faria D, Alves MJN, Hagen L, Sharma A, Slupphaug G, Moreira JBN, Wisloff U, Hirshman MF, Negrão CE, de Castro G Jr, Chammas R, Swoboda KJ, Ruas JL, Goodyear LJ, and Brum PC
- Subjects
- Animals, Biomarkers, COP9 Signalosome Complex genetics, Cachexia etiology, Cachexia metabolism, Cell Line, Tumor, Cytokines metabolism, Disease Models, Animal, Energy Metabolism, Gene Knockdown Techniques, Humans, Male, Mice, Muscle Fibers, Skeletal metabolism, Muscular Atrophy etiology, Muscular Atrophy metabolism, Myoblasts metabolism, Neoplasms complications, Oxidation-Reduction, Proteomics methods, Rats, Receptors, TNF-Related Apoptosis-Inducing Ligand genetics, Receptors, TNF-Related Apoptosis-Inducing Ligand metabolism, Repressor Proteins genetics, Signal Transduction, COP9 Signalosome Complex metabolism, Muscle, Skeletal metabolism, Neoplasms metabolism, Oxidative Stress, Physical Conditioning, Animal, Repressor Proteins metabolism
- 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., (Copyright © 2020 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
- Published
- 2020
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