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

School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil.
PLoS ONE (Impact Factor: 3.23). 08/2012; 7(8):e41701. DOI: 10.1371/journal.pone.0041701
Source: PubMed


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.

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    • "The chymotrypsin-like activity of proteasome 20S of the plantaris muscle was assessed using a fluorometric assay based on the fluorogenic substrate N-succinyl-Leu-Leu-Val-Tyr-7-amido-4- methylcoumarin (Suc-LLVY-AMC; Enzo Life Sciences item #P802- 0005), as previously described (Cunha et al. 2012). Protein (50 g) from each sample was incubated in 200 L of 10 mmol/L 3-(Nmorpholino )propanesulfonic acid, pH 7.5, containing 25 mol/L Suc-LLVY-AMC as well as 25 mol/L ATP and 5 mmol/L Mg 2+ , which function as peptidase cofactors. "
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    ABSTRACT: Sleep deprivation (SD) can induce muscle atrophy. We aimed to investigate the changes underpinning SD-induced muscle atrophy and the impact of this condition on rats that were previously submitted to resistance training (RT). Adult male Wistar EPM-1 rats were randomly allocated into 1 of 5 groups: control, sham, SD (for 96 h), RT, and RT+SD. The major outcomes of this study were muscle fiber cross-sectional area (CSA), anabolic and catabolic hormone profiles, and the abundance of select proteins involved in muscle protein synthesis and degradation pathways. SD resulted in muscle atrophy; however, when SD was combined with RT, the reduction in muscle fiber CSA was attenuated. The levels of IGF-1 and testosterone were reduced in SD animals, and the RT+SD group had higher levels of these hormones than the SD group. Corticosterone was increased in the SD group compared with the control group, and this increase was minimized in the RT+SD group. The increases in corticosterone concentrations paralleled changes in the abundance of ubiquitinated proteins and the autophagic proteins LC3 and p62/SQSTM1, suggesting that corticosterone may trigger these changes. SD induced weight loss, but this loss was minimized in the RT+SD group. We conclude that SD induced muscle atrophy, probably because of the increased corticosterone and catabolic signal. High-intensity RT performed before SD was beneficial in containing muscle loss induced by SD. It also minimized the catabolic signal and increased synthetic activity, thereby minimizing the body's weight loss.
    Applied Physiology Nutrition and Metabolism 07/2015; 40(11):150721103636004. DOI:10.1139/apnm-2015-0061 · 2.34 Impact Factor
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    • "plantaris) that are more prone to atrophy and have less antioxidant defense compared with oxidative ones. ROS are able to modulate the UPS activation [44], which is the major responsible for degradation of skeletal muscle proteins in various atrophying states [9], including HF [8] [41]. Our data corroborate the previously reported association between oxidative stress and UPS activation in the skeletal muscle, and here we extend our findings to the contribution of NADPH oxidase on MI-induced UPS hyperactivation, since apocynin treatment prevented the increased UPS activation in the plantaris muscle. "
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    ABSTRACT: Background: Skeletal muscle wasting is associated with poor prognosis and increased mortality in heart failure (HF) patients. Glycolytic muscles are more susceptible to catabolic wasting than oxidative ones. This is particularly important in HF since glycolytic muscle wasting is associated with increased levels of reactive oxygen species (ROS). However, the main ROS sources involved in muscle redox imbalance in HF have not been characterized. Therefore, we hypothesized that NADPH oxidases would be hyperactivated in the plantaris muscle of infarcted rats, contributing to oxidative stress and hyperactivation of the ubiquitin-proteasome system (UPS), ultimately leading to atrophy. Methods: Rats were submitted to myocardial infarction (MI) or Sham surgery. Four weeks after surgery, MI and Sham groups underwent eight weeks of treatment with apocynin, a NADPH oxidase inhibitor, or placebo. NADPH oxidase activity, oxidative stress markers, NF-κB activity, p38 MAPK phosphorylation, mRNA and sarcolemmal protein levels of NADPH oxidase components, UPS activation and fiber cross-sectional area were assessed in the plantaris muscle. Results: The plantaris of MI rats displayed atrophy associated with increased Nox2 mRNA and sarcolemmal protein levels, NADPH oxidase activity, ROS production, lipid hydroperoxides levels, NF-κB activity, p38 MAPK phosphorylation and UPS activation. NADPH oxidase inhibition by apocynin prevented MI-induced skeletal muscle atrophy by reducing ROS production, NF-κB hyperactivation, p38 MAPK phosphorylation and proteasomal hyperactivity. Conclusion: Our data provide evidence for NADPH oxidase hyperactivation as an important source of ROS production leading to plantaris atrophy in heart failure rats, suggesting that this enzyme complex plays key role in skeletal muscle wasting in HF.
    International Journal of Cardiology 07/2014; 175(3). DOI:10.1016/j.ijcard.2014.06.046 · 4.04 Impact Factor
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    • "Similarly, the beneficial effects of endurance training have been demonstrated in the transgenic nemaline mouse model of the extensor digitorum longus (EDL) muscle, revealing a novel myofiber repair mechanism [31]. Prevention of oxidative stress and overactivity in the ubiquitin-proteasome system in heart failure-induced myopathy in a mouse model was recently reported [32]. Endurance training also prevented TNF-α induced loss of force in the diaphragm of C57Bl6 mice [33]. "
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    ABSTRACT: The therapeutic effects of exercise resistance and endurance training in the alleviation of muscle hypertrophy/atrophy should be considered in the management of patients with advanced neuromuscular diseases. Patients with progressive neuromuscular diseases often experience muscle weakness, which negatively impact independence and quality of life levels. Mutations in the valosin containing protein (VCP) gene lead to Inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD) and more recently affect 2% of amyotrophic lateral sclerosis (ALS)-diagnosed cases. The present investigation was undertaken to examine the effects of uphill and downhill exercise training on muscle histopathology and the autophagy cascade in an experimental VCP mouse model carrying the R155H mutation. Progressive uphill exercise in VCP(R155H/+) mice revealed significant improvement in muscle strength and performance by grip strength and Rotarod analyses when compared to the sedentary mice. In contrast, mice exercised to run downhill did not show any significant improvement. Histologically, the uphill exercised VCP(R155H/+) mice displayed an improvement in muscle atrophy, and decreased expression levels of ubiquitin, P62/SQSTM1, LC3I/II, and TDP-43 autophagy markers, suggesting an alleviation of disease-induced myopathy phenotypes. There was also an improvement in the Paget-like phenotype. Collectively, our data highlights that uphill exercise training in VCP(R155H/+) mice did not have any detrimental value to the function of muscle, and may offer effective therapeutic options for patients with VCP-associated diseases.
    PLoS ONE 10/2013; 8(10):e76187. DOI:10.1371/journal.pone.0076187 · 3.23 Impact Factor
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