Abstract
BackgroundHeart 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 FindingsTime-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.ConclusionsCollectively, 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.
Highlights
Heart failure (HF) is a syndrome of poor prognosis characterized by exercise intolerance, early fatigue and skeletal myopathy marked by atrophy and shift toward fast twitch fibers [1,2], which may culminate in cardiac cachexia, an underestimated problem for HF prognosis and healthcare expenditure [3]
aerobic exercise training (AET) attenuates skeletal muscle proteasome activity paralleled by improved aerobic capacity in HF patients, which is not achieved by drug treatment itself
HF is a syndrome of poor prognosis characterized by exercise intolerance, early fatigue and skeletal myopathy marked by atrophy and shift toward fast twitch fibers [1,2], which may culminate in cardiac cachexia, an underestimated problem for HF prognosis and healthcare expenditure [3]
Summary
HF is a syndrome of poor prognosis characterized by exercise intolerance, early fatigue and skeletal myopathy marked by atrophy and shift toward fast twitch fibers [1,2], which may culminate in cardiac cachexia, an underestimated problem for HF prognosis and healthcare expenditure [3]. Increased protein degradation, circulating proinflammatory cytokines and oxidative stress are common features of systemic diseases-induced skeletal muscle wasting, including HF [5,6,7,8]. UPS is a major proteolytic pathway responsible for disposal of damaged proteins, which accumulate in skeletal myopathies [9]. Aggravation of skeletal muscle atrophy is associated with UPS overactivation [9]. Atrogin-1 and MuRF1, E3 ligases driving conjugation of ubiquitin chains to proteasome substrates, are directly associated with but required for skeletal muscle atrophy [10,11], highlighting the importance of UPS beyond associative findings. We hypothesized that HF would increase oxidative stress and ubiquitin-proteasome system (UPS) activation in skeletal muscle of sympathetic hyperactivity mouse model. We tested the hypothesis that aerobic exercise training (AET) would reestablish UPS activation in mice and human HF
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