Aline Villa Nova Bacurau

Aerobic exercise training improves skeletal muscle function and Ca2+ handling-related protein expression in sympathetic hyperactivity-induced heart failure

The cellular mechanisms of positive effects associated with aerobic exercise training on overall intrinsic skeletal muscle changes in heart failure (HF) remain unclear. We investigated potential Ca2+ abnormalities in skeletal muscles comprising different fiber compositions and investigated whether aerobic exercise training would improve muscle function in a genetic model of sympathetic hyperactivity-induced HF. A cohort of male 5-mo-old wild-type (WT) and congenic alpha2A/alpha2C adrenoceptor knockout (ARKO) mice in a C57BL/6J genetic background were randomly assigned into untrained and trained groups. Exercise training consisted of a 8-wk running session of 60 min, 5 days/wk (from 5 to 7 mo of age). After completion of the exercise training protocol, exercise tolerance was determined by graded treadmill exercise test, muscle function test by Rotarod, ambulation and resistance to inclination tests, cardiac function by echocardiography, and Ca2+ handling-related protein expression by Western blot. alpha2A/alpha2CARKO mice displayed decreased ventricular function, exercise intolerance, and muscle weakness paralleled by decreased expression of sarcoplasmic Ca2+ release-related proteins [alpha1-, alpha2-, and beta1-subunits of dihydropyridine receptor (DHPR) and ryanodine receptor (RyR)] and Ca2+ reuptake-related proteins [sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)1/2 and Na+/Ca2+ exchanger (NCX)] in soleus and plantaris. Aerobic exercise training significantly improved exercise tolerance and muscle function and reestablished the expression of proteins involved in sarcoplasmic Ca2+ handling toward WT levels. We provide evidence that Ca2+ handling-related protein expression is decreased in this HF model and that exercise training improves skeletal muscle function associated with changes in the net balance of skeletal muscle Ca2+ handling proteins.

Aerobic exercise training in heart failure: impact on sympathetic hyperactivity and cardiac and skeletal muscle function

Heart failure is a common endpoint for many forms of cardiovascular disease and a significant cause of morbidity and mortality. Chronic neurohumoral excitation (i.e., sympathetic hyperactivity) has been considered to be a hallmark of heart failure and is associated with a poor prognosis, cardiac dysfunction and remodeling, and skeletal myopathy. Aerobic exercise training is efficient in counteracting sympathetic hyperactivity and its toxic effects on cardiac and skeletal muscles. In this review, we describe the effects of aerobic exercise training on sympathetic hyperactivity, skeletal myopathy, as well as cardiac function and remodeling in human and animal heart failure. We also discuss the mechanisms underlying the effects of aerobic exercise training.

Aerobic exercise training upregulates skeletal muscle calpain and ubiquitin-proteasome systems in healthy mice

Aerobic exercise training (AET) is an important mechanical stimulus that modulates skeletal muscle protein turnover, leading to structural rearrangement. Since the ubiquitin-proteasome system (UPS) and calpain system are major proteolytic pathways involved in protein turnover, we aimed to investigate the effects of intensity-controlled AET on the skeletal muscle UPS and calpain system and their association to training-induced structural adaptations. Long-lasting effects of AET were studied in C57BL/6J mice after 2 or 8 wk of AET. Plantaris cross-sectional area (CSA) and capillarization were assessed by myosin ATPase staining. mRNA and protein expression levels of main components of the UPS and calpain system were evaluated in plantaris by real-time PCR and Western immunoblotting, respectively. No proteolytic system activation was observed after 2 wk of AET. Eight weeks of AET resulted in improved running capacity, plantaris capillarization, and CSA. Muscle RING finger-1 mRNA expression was increased in 8-wk-trained mice. Accordingly, elevated 26S proteasome activity was observed in the 8-wk-trained group, without accumulation of ubiquitinated or carbonylated proteins. In addition, calpain abundance was increased by 8 wk of AET, whereas no difference was observed in its endogenous inhibitor calpastatin. Taken together, our findings indicate that skeletal muscle enhancements, as evidenced by increased running capacity, plantaris capillarization, and CSA, occurred in spite of the upregulated UPS and calpain system, suggesting that overactivation of skeletal muscle proteolytic systems is not restricted to atrophying states. Our data provide evidence for the contribution of the UPS and calpain system to metabolic turnover of myofibrillar proteins and skeletal muscle adaptations to AET.

Effect of a High-Intensity Exercise Training on the Metabolism and Function of Macrophages and Lymphocytes of Walker 256 Tumor–Bearing Rats

Epidemiologic studies suggest that moderately intense training promotes augmented immune function, whereas strenuous exercise can cause immunosupression. Because the combat of cancer requires high immune function, high-intensity exercise could negatively affect the host organism; however, despite the epidemiologic data, there is a lack of experimental evidence to show that high-intensity training is harmful to the immune system. Therefore, we tested the influence of high-intensity treadmill training (10 weeks, 5 days/week, 30 mins/day, 85% VO2max) on immune system function and tumor development in Walker 256 tumor–bearing Wistar rats. The metabolism of glucose and glutamine in lymphocytes and macrophages was assessed, in addition to some functional parameters such as hydrogen peroxide production, phagocytosis, and lymphocyte proliferative responses. The metabolism of Walker 256 cells was also investigated. Results demonstrated that high-intensity training increased the life span of tumor-bearing rats, promoted a reduction in tumor mass, and prevented indicators of cachexia. Several changes, such as a reduction in body weight and food intake and activation of glutamine metabolism in macrophages and lymphocytes induced by the presence of Walker 256 tumor, were prevented by high intensity training. The reduction in tumor growth was associated with an impairment of tumor cell glucose and glutamine metabolism. These data suggest that high-intensity exercise training may be a viable strategy against tumors.

Autophagy Signaling in Skeletal Muscle of Infarcted Rats

Background Heart failure (HF)-induced skeletal muscle atrophy is often associated to exercise intolerance and poor prognosis. Better understanding of the molecular mechanisms underlying HF-induced muscle atrophy may contribute to the development of pharmacological strategies to prevent or treat such condition. It has been shown that autophagy-lysosome system is an important mechanism for maintenance of muscle mass. However, its role in HF-induced myopathy has not been addressed yet. Therefore, the aim of the present study was to evaluate autophagy signaling in myocardial infarction (MI)-induced muscle atrophy in rats. Methods/Principal Findings Wistar rats underwent MI or Sham surgeries, and after 12 weeks were submitted to echocardiography, exercise tolerance and histology evaluations. Cathepsin L activity and expression of autophagy-related genes and proteins were assessed in soleus and plantaris muscles by fluorimetric assay, qRT-PCR and immunoblotting, respectively. MI rats displayed exercise intolerance, left ventricular dysfunction and dilation, thereby suggesting the presence of HF. The key findings of the present study were: a) upregulation of autophagy-related genes (GABARAPL1, ATG7, BNIP3, CTSL1 and LAMP2) was observed only in plantaris while muscle atrophy was observed in both soleus and plantaris muscles, and b) Cathepsin L activity, Bnip3 and Fis1 protein levels, and levels of lipid hydroperoxides were increased specifically in plantaris muscle of MI rats. Conclusions Altogether our results provide evidence for autophagy signaling regulation in HF-induced plantaris atrophy but not soleus atrophy. Therefore, autophagy-lysosome system is differentially regulated in atrophic muscles comprising different fiber-types and metabolic characteristics.

Skeletal myopathy in heart failure: effects of aerobic exercise training

What is the topic of this review? This symposium report addresses the effects of aerobic exercise training on skeletal muscle myopathy induced by heart failure (HF), with emphasis on the mechanisms involved in muscle atrophy. What advances does it highlight? It highlights the therapeutic effect of aerobic exercise training to combat skeletal myopathy in HF. Our results demonstrated that aerobic exercise training re‐established normal redox balance and prevented increased protein degradation by the ubiquitin–proteasome system, thereby preserving skeletal muscle mass in experimental models of HF. Our findings contribute to a better understanding of the mechanisms involved in skeletal myopathy in HF and the effects of training.

Long-Term Aerobic Exercise Protects against Cisplatin- Induced Nephrotoxicity by Modulating the Expression of IL-6 and HO-1

Nephrotoxicity is substantial side effect for 30% of patients undergoing cancer therapy with cisplatin and may force them to change or even abandon the treatment. Studies regarding aerobic exercise have shown its efficacy for the treatment of many types of diseases and its capacity to reduce tumors. However, little is known about the impact of physical exercise on cisplatin-induced acute kidney injury (AKI). In the present study, our aim was to investigate the role of physical exercise in AKI induced by cisplatin. We submitted C57Bl6 male mice to seven weeks of chronic exercise on a training treadmill and treated them with single i.p. injection of cisplatin (20 mg/kg) in the last week. Exercise efficacy was confirmed by an increased capillary-to-fiber ratio in the gastrocnemius muscle of exercised groups (EX and CIS-EX). The group submitted to exercise before cisplatin administration (CIS-EX) exhibited less weight loss and decreased serum urea levels compared to the cisplatin group (CIS). Exercise also showed a protective role against cisplatin-induced cell death in the kidney. The CIS-EX group showed a lower inflammatory response, with less TNF and IL-10 expression in the kidney and serum. In the same group, we observed an increase of IL-6 and HO-1 expression in the kidney. Taken together, our results indicate that chronic aerobic exercise is able to attenuate AKI by inducing IL-6 and HO-1 production, which results in lower inflammatory and apoptotic profiles in the kidney.

Effects of dietary restriction or swimming on lymphocytes and macrophages functionality from old rats

Although aging compromises the functionality of macrophages (MΦ) and lymphocytes (LY), and dietary restriction (DR) and exercise partially counterbalance immunosenescence, it is unknown what effects of both strategies have on the functionality of these immune cells. Rats were randomly distributed into adult control (AD), older group (OLD), older submitted to 50% of DR (DR) and older submitted to swimming (EX) (n = 10 in each group). The function of immune cells (proliferative index, phagocytic capacity and H2O2 production), the weight and protein content of lymphoid organs (thymus and spleen), plasma glutamine concentration, interleukins (IL-1, IL-2, IL-6) and, immunoglobulins (IgA and IgG) were analysed. There was an increase of 74% in body weight in aged animals as compared with the AD group, while body weight reduced 19% in the DR as compared with the OLD group. Swimming training stimulated MΦ phagocytosis, while the EX group presented a decrease of the proliferative capacity of LY from the mesenteric lymph nodes (44% and 62%, respectively), when stimulated with ConA and LPS as compared with the old rats. These data demonstrated that DR and exercise affects differentially MΦ and LY function.

Exercise training improves neurovascular control and calcium cycling gene expression in patients with heart failure with cardiac resynchronization therapy

Heart failure (HF) is characterized by decreased exercise capacity, attributable to neurocirculatory and skeletal muscle factors. Cardiac resynchronization therapy (CRT) and exercise training have each been shown to decrease muscle sympathetic nerve activity (MSNA) and increase exercise capacity in patients with HF. We hypothesized that exercise training in the setting of CRT would further reduce MSNA and vasoconstriction and would increase Ca2+-handling gene expression in skeletal muscle in patients with chronic systolic HF. Thirty patients with HF, ejection fraction <35% and CRT for 1 mo, were randomized into two groups: exercise-trained (ET, n = 14) and untrained (NoET, n = 16) groups. The following parameters were compared at baseline and after 4 mo in each group: V̇o2 peak, MSNA (microneurography), forearm blood flow, and Ca2+-handling gene expression in vastus lateralis muscle. After 4 mo, exercise duration and V̇o2 peak were significantly increased in the ET group (P = 0.04 and P = 0.01, respectively), but not in the NoET group. MSNA was significantly reduced in the ET (P = 0.001), but not in NoET, group. Similarly, forearm vascular conductance significantly increased in the ET (P = 0.0004), but not in the NoET, group. The expression of the Na+/Ca2+ exchanger (P = 0.01) was increased, and ryanodine receptor expression was preserved in ET compared with NoET. In conclusion, the exercise training in the setting of CRT improves exercise tolerance and neurovascular control and alters Ca2+-handling gene expression in the skeletal muscle of patients with systolic HF. These findings highlight the importance of including exercise training in the treatment of patients with HF even following CRT.