Exercise Training Prevents Oxidative Stress and Ubiquitin-Proteasome System Overactivity and Reverse Skeletal Muscle Atrophy in Heart Failure
Cunha, TF; Bacurau, AVN; Moreira, JBN; Paixao, NA; Campos, JC; Ferreira, JCB; Leal, ML; Negrao, CE; Moriscot, AS; Wisløff, Ulrik; Brum, PC
Journal article, Peer reviewed
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http://hdl.handle.net/11250/2365428Utgivelsesdato
2012Metadata
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Background: 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.
Methods/Principal Findings: 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 7th 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.
Conclusions: 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.