Contribution of oxidative stress to NF-kB, FOXO and MAPK signaling pathway activation in atrophy induced by heart failure: role of aerobic exercise training

Author(s)

Telma Fátima da Cunha

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Escola de Educação Física e Esportes (EEFE/BT)
• Defense date: 2015-01-20

Examining board members

Patricia Chakur Brum; Edilamar Menezes de Oliveira; Paulo Rizzo Ramires; Leonardo dos Reis Silveira

• Advisor: Patricia Chakur Brum; Julio Cesar Batista Ferreira

Abstract

About 40% of human body mass consists of skeletal muscles, which are involved in all aspects of movement including breathing, eating, posture, walking and reflexes. Skeletal muscle is also important as a source of heat generation and as a regulator of intermediary metabolism. Loss of skeletal muscle mass and function (skeletal muscle atrophy) leads to several functional impairments, affecting health and quality of life. It occurs in several chronic diseases such as cancer, diabetes and heart failure. In heart failure, atrophy is considered an independent predictor of poor prognosis. Oxidative stress has a crucial role in atrophy, activating different signaling pathways capable of stimulating the ubiquitin proteasome system to degrade proteins. In this study, we investigated the oxidative stress contribution to NF-kB, FOXO and MAPK signaling pathway activation in heart failure-induced atrophy. To better understand the mechanisms involved with oxidative stress and signaling pathways activation in atrophy, we have used C2C12 skeletal muscle cells. We observed that, even in high hydrogen peroxide concentrations, oxidative stress increased proteasome activity, phosphorylated p38 and NF-kB protein expression, causing myotubes atrophy. In an experimental heart failure model of infarcted rats, we evaluated plantaris muscle and verified a reduced cross sectional area, accompanied by increased systemic inflammation, p-38 protein expression and increased both NF-kB and proteasome activities. As aerobic exercise training causes a lot of beneficial effects on skeletal muscle structure and function in chronic diseases, we submitted infarcted rats to 8 weeks of aerobic exercise training on a treadmill. Aerobic exercise training prevented atrophy by reducing inflammation and both NF-kB and proteasome activities. Collectively, our data suggest a differentiated activation by oxidative stress in muscle cells and animal models. In the first case, protein degradation was involved with protein quality control; and, in the other, oxidative stress is a second messenger, stimulating protein degradation to provide substrates to metabolism. Aerobic exercise training re-established proteasome activity by reducing inflammation and NF-kB activity, preventing muscle atrophy (AU)

• FAPESP's process: 11/00728-9 - Oxidative stress contribution to NF-kB, FOXO and MAPK pathways signaling activation in skeletal muscle atrophy associated to heart failure: effect of aerobic training and N-acetylcysteine treatment
• Grantee: Telma Fátima da Cunha Moraes
• Support Opportunities: Scholarships in Brazil - Doctorate