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

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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.

• Tipo de documento: Artigo Científico
• Fonte: MOLECULAR METABOLISM; v. 39, p. 17-pg., 2020-09-01.

Resumo

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)

• Processo FAPESP: 16/50336-3 - Predicting survival in non-small-cell lung cancer: a link between cancer cachexia, cardiorespiratory fitness and cancer immune surveillance?
• Beneficiário: Patricia Chakur Brum
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 14/03016-8 - Caquexia do câncer: efeitos do treinamento físico aeróbio sobre o músculo esquelético em modelo animal
• Beneficiário: Christiano Robles Rodrigues Alves
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 16/20187-6 - Caquexia em pacientes com carcinoma pulmonar de células não pequenas: influência da aptidão física sobre o prognóstico
• Beneficiário: Willian das Neves Silva
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 12/25240-1 - Efeitos do treinamento físico aeróbio intervalado em alta intensidade no músculo esquelético de ratos inoculados com o tumor Walker 256
• Beneficiário: Christiano Robles Rodrigues Alves
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Mestrado
• Processo FAPESP: 16/01478-0 - Mecanismos moleculares da caquexia do câncer: explorando o papel da COPS2
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• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado Direto
• Processo FAPESP: 15/22814-5 - Câncer e coração: novos paradigmas de diagnóstico e tratamento
• Beneficiário: Carlos Eduardo Negrão
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 12/02528-0 - Efeitos do treinamento físico aeróbio intervalado em alta intensidade no músculo esquelético de ratos inoculados com o tumor Walker 256
• Beneficiário: Christiano Robles Rodrigues Alves
• Modalidade de apoio: Bolsas no Brasil - Mestrado