Exercise training decreases NADPH oxidase activity and restores skeletal muscle mass in heart failure rats

Abstract

We have recently demonstrated that NADPH oxidase hyperactivity, NF-κB activation, and increased p38 phosphorylation lead to atrophy of glycolytic muscle in heart failure (HF). Aerobic exercise training (AET) is an efficient strategy to counteract skeletal muscle atrophy in this syndrome. Therefore, we tested whether AET would regulate muscle redox balance and protein degradation by decreasing NADPH oxidase hyperactivity and reestablishing NF-κB signaling, p38 phosphorylation, and proteasome activity in plantaris muscle of myocardial infarcted-induced HF (MI) rats. Thirty-two male Wistar rats underwent MI or fictitious surgery (SHAM) and were randomly assigned into untrained (UNT) and trained (T; 8 wk of AET on treadmill) groups. AET prevented HF signals and skeletal muscle atrophy in MI-T, which showed an improved exercise tolerance, attenuated cardiac dysfunction and increased plantaris fiber cross-sectional area. To verify the role of inflammation and redox imbalance in triggering protein degradation, circulating TNF-α levels, NADPH oxidase profile, NF-κB signaling, p38 protein levels, and proteasome activity were assessed. MI-T showed a reduced TNF-α levels, NADPH oxidase activity, and Nox2 mRNA expression toward SHAM-UNT levels. The rescue of NADPH oxidase activity induced by AET in MI rats was paralleled by reducing nuclear binding activity of the NF-κB, p38 phosphorylation, atrogin-1, mRNA levels, and 26S chymotrypsin-like proteasome activity. Taken together our data provide evidence for AET improving plantaris redox homeostasis in HF associated with a decreased NADPH oxidase, redox-sensitive proteins activation, and proteasome hyperactivity further preventing atrophy. These data reinforce the role of AET as an efficient therapy for muscle wasting in HF. This study demonstrates, for the first time, the contribution of aerobic exercise training (AET) in decreasing muscle NADPH oxidase activity associated with reduced reactive oxygen species production and systemic inflammation, which diminish NF-κB overactivation, p38 phosphorylation, and ubiquitin proteasome system hyperactivity. These molecular changes counteract plantaris atrophy in trained myocardial infarction-induced heart failure rats. Our data provide new evidence into how AET may regulate protein degradation and thus prevent skeletal muscle atrophy.

The Emerging Roles of Nicotinamide Adenine Dinucleotide Phosphate Oxidase 2 in Skeletal Muscle Redox Signaling and Metabolism

“…For instance, a recent study of cardiac cachexia in a rat model of heart failure (HF) demonstrated increased NOX2 and p47phox protein expression and NOX2 activity in isolated membrane fractions accompanied by NF-jB activation and increased p38 phosphorylation and atrophy of glycolytic plantaris muscle. In this model, the muscle wasting and the NOX2 complex activity were reduced by 8 weeks of treadmill exercise training, suggesting that NOX2 may be a good candidate drug target for treating cardiac cachexia and perhaps other types of muscle wasting (72). In contrast, a study investigating mouse cancer cachexia reported decreased mRNA expression of multiple NOX2 subunits and antioxidant defense enzymes commensurate with increased DHE fluorescence in skeletal muscle (336), suggesting that decreased antioxidant defense rather than increased NOX2 activity caused oxidative stress in that model.…”

Role of Oxidative Stress as Key Regulator of Muscle Wasting during Cachexia

“…Interestingly, O 2 · − generated from Nox has been implicated in progressive skeletal muscle damage [ 86 ]. Recent evidence demonstrated that NADPH oxidase overactivity leads to atrophy of glycolytic muscle in a rat model of heart failure (HF) [ 87 ]. Interestingly, the mechanism also involved the NF- κ B activation and increased p38 phosphorylation and was reduced by aerobic exercise training, suggesting that NADPH oxidase activity can be a good candidate for targeting and treating the muscle wasting [ 87 ].…”

Deletion of NAD(P)H Oxidase 2 Prevents Angiotensin II-Induced Skeletal Muscle Atrophy

“…Additionally, AII activates NAD(P)H oxidase (Nox) and increases Nox-derived ROS via the AII type I receptor [ 13 ]. Previous studies reported that gene expression of Nox2 was increased in the skeletal muscle from mice with myocardial infarction [ 14 – 16 ]. Nox2 is the main isoform of NADPH oxidase responsible for superoxide anion generation [ 17 ].…”