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

Author(s):Show less -

Alves, Christiano R. R. ; das Neves, Willian ; de Almeida, Ney R. ; Eichelberger, Eric J. ; Jannig, Paulo R. ; Voltarelli, Vanessa A. ; Tobias, Gabriel C. ; Bechara, Luiz R. G. ; Faria, Daniele de Paula ; Alves, Maria J. N. ; Hagen, Lars ; Sharma, Animesh ; Slupphaug, Geir ; Moreira, Jose B. N. ; Wisloff, Ulrik ; Hirshman, Michael F. ; Negrao, Carlos E. ; de Castro, Gilberto, Jr. ; Chammas, Roger ; Swoboda, Kathryn J. ; Ruas, Jorge L. ; Goodyear, Laurie J. ; Brum, Patricia C.

• Document type: Journal article
• Source: MOLECULAR METABOLISM; v. 39, p. 17-pg., 2020-09-01.

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 agematched 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. (C) 2020 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). (AU)

• FAPESP's process: 16/50336-3 - Predicting survival in non-small-cell lung cancer: a link between cancer cachexia, cardiorespiratory fitness and cancer immune surveillance?
• Grantee: Patricia Chakur Brum
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/03016-8 - Cancer cachexia: effects of aerobic physical training on skeletal muscle in animal model
• Grantee: Christiano Robles Rodrigues Alves
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 16/20187-6 - Caquexia in non-small cell lung cancer patient: physical fitness influence on prognosis
• Grantee: Willian das Neves Silva
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 12/25240-1 - Effects of high-intensity interval training on skeletal muscle of Walker 256 tumor-bearing rats
• Grantee: Christiano Robles Rodrigues Alves
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• FAPESP's process: 16/01478-0 - Molecular mechanisms underlying cancer cachexia: exploring the role of COPS2
• Grantee: Christiano Robles Rodrigues Alves
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• FAPESP's process: 15/22814-5 - Cancer and heart: new paradigms of diagnosis and treatment
• Grantee: Carlos Eduardo Negrão
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/02528-0 - Effects of high-intensity physical training on skeletal muscle of Walker 256 tumor-bearing rats
• Grantee: Christiano Robles Rodrigues Alves
• Support Opportunities: Scholarships in Brazil - Master