Journal Article

Exercise Training Prevents Oxidative Stress and Ubiquitin-Proteasome System Overactivity and Reverse Skeletal Muscle Atrophy in Heart Failure

Bacurau, Aline V. N., Negrão, Carlos E., Cunha, Telma F., Leal, Marcelo L., Brum, Patricia C., Wisløff, Ulrik, Moreira, Jose B. N., Ferreira, Julio C. B., Paixão, Nathalie A., Campos, Juliane C., Moriscot, Anselmo S.

2012

Overview

Heart failure (HF) is known to lead to skeletal muscle atrophy and dysfunction. However, intracellular mechanisms underlying HF-induced myopathy are not fully understood. We hypothesized that HF would increase oxidative stress and ubiquitin-proteasome system (UPS) activation in skeletal muscle of sympathetic hyperactivity mouse model. We also tested the hypothesis that aerobic exercise training (AET) would reestablish UPS activation in mice and human HF. Time-course evaluation of plantaris muscle cross-sectional area, lipid hydroperoxidation, protein carbonylation and chymotrypsin-like proteasome activity was performed in a mouse model of sympathetic hyperactivity-induced HF. At the 7(th) month of age, HF mice displayed skeletal muscle atrophy, increased oxidative stress and UPS overactivation. Moderate-intensity AET restored lipid hydroperoxides and carbonylated protein levels paralleled by reduced E3 ligases mRNA levels, and reestablished chymotrypsin-like proteasome activity and plantaris trophicity. In human HF (patients randomized to sedentary or moderate-intensity AET protocol), skeletal muscle chymotrypsin-like proteasome activity was also increased and AET restored it to healthy control subjects' levels. Collectively, our data provide evidence that AET effectively counteracts redox imbalance and UPS overactivation, preventing skeletal myopathy and exercise intolerance in sympathetic hyperactivity-induced HF in mice. Of particular interest, AET attenuates skeletal muscle proteasome activity paralleled by improved aerobic capacity in HF patients, which is not achieved by drug treatment itself. Altogether these findings strengthen the clinical relevance of AET in the treatment of HF.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Activation / Aerobic capacity / Age / Aged / Aged, 80 and over / Analysis / Animals / Antioxidants / Atrophy / Biology / Carbonyls / Chronic illnesses / Chymotrypsin / Delivery services / Ethics / Exercise / Exercise Therapy / Female / Fitness training programs / Heart diseases / Heart failure / Heart Failure - complications / Heart Failure - genetics / Heart Failure - metabolism / Heart Failure - physiopathology / Heart Failure - therapy / Humans / Hyperactivity / Intolerance / Ligases / Lipid peroxidation / Lipid Peroxidation - genetics / Male / Medicine / Mice / Mice, Knockout / Model testing / mRNA / Muscle Proteins - genetics / Muscle Proteins - metabolism / Muscles / Muscular Atrophy - etiology / Muscular Atrophy - genetics / Muscular Atrophy - metabolism / Muscular Atrophy - physiopathology / Muscular Atrophy - therapy / Musculoskeletal system / Myopathy / Oxidative Stress / Patients / Physical Conditioning, Animal / Physical education / Physical training / Proteasome Endopeptidase Complex - genetics / Proteasome Endopeptidase Complex - metabolism / Proteasomes / Rodents / Skeletal muscle / Training / Ubiquitin / Ubiquitin - genetics / Ubiquitin - metabolism / Ubiquitin-protein ligase