Effect of aerobic exercise training on cGMP levels and blood pressure in treated hypertensive postmenopausal women

Abstract The second messenger cGMP has been largely studied as a therapeutic target in a variety of disorders such as erectile dysfunction, arterial hypertension and heart failure. Evidence has shown thatcGMP activators are less efficient in estrogen-deficiency animals, but no studies exist involving non-pharmacological approacheson NO/cGMP signaling pathway in hypertensive postmenopausal women. The aim of this study is to examine NO/cGMP pathway, redox state and blood pressure in trained treatedhypertensive (HT) postmenopausal women comparing with normotensive (NT) group. The rationale for that is most of HT patients is encouraged by physician to perform exercise associated with pharmacological treatments.Aerobic exercise training (AET) consisted of 24 sessions, 3 times/week.Parameters were evaluated at baseline and after AET for both groups (HT=28; NT=33).In treatedHT group, AET was significantly effective in increasing cGMP concentrations (28%) accompanied by an up-regulation of SOD (97%) and catalase activity (37%). In NT group, we found an increasein SOD activity (58%). TreatedHT postmenopausal women were still responsive to AET increasing cGMP levels and up-regulating antioxidant system. It should also be emphasized that these findings provide information on the circulating biomarkers that might delay the developing of cardiovascular events in this particular population

Circulating concentrations of adipocytokines and their receptors in the isolate corpus cavernosum and femoral artery from trained rats on a high-fat diet

The aim of the present study was to evaluate different signaling pathways by which exercise training would interfere in endothelial function in obesity. Therefore, we examined adipocytokine levels and their receptors in the corpus cavernosum and femoral artery from trained rats on a high-fat diet. Methods: Functional experiments were performed in control sedentary and trained rats, and sedentary (h-SD) and trained male Wistar rats on a high-fat diet (h-TR). Nitric oxide (NO) and reactive oxygen species (ROS) were evaluated in vascular tissue. Circulating adipocytokines and their receptors were analyzed. Results: In the h-SD group, the maximal responses to acetylcholine (ACh) were reduced in the femoral artery and corpus cavernosum as well as the electrical field stimulation, accompanied by an increase in circulating insulin, leptin, TNF-alpha, MCP-1, and PAI-1. Downregulation of ObR protein expression in the femoral artery was observed without alterations in AdipoR1 and TNFR1 in both prepara-tions. A positive effect was observed in the h-TR group regarding the relaxation response to ACh and circulating adipocytokines, resulting in increased NO production and reduced ROS generation. Exercise restored the ObR protein expression only in the femoral artery. Conclusion: Aerobic exercise training ameliorated the inflammatory adipocytokines and restored the relaxation responses in the corpus cavernosum and femoral artery in rats on a high-fat diet5413350CNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO441514/2014-62013/26886-

Perivascular adipose tissue and vascular responses in healthy trained rats

Aims: The importance of perivascular adipose tissue (PVAT) in vascular function has recently been recognized. The aim of the study was to investigate the effects of exercise training on anticontractile responses of periaortic adipose tissue.Main methods: Male Wistar rats were divided into sedentary (SD) and trained (TR). Running training was performed for 60 min/day, 5 days/week, for 8 weeks. Concentration-response curves to acetylcholine (ACh), sodium nitroprusside (SNP), phenylephrine (PHE) and serotonin (5-HT) were obtained in aortic rings without (PVAT-) or with (PVAT+) PVAT. The protein expressions of eNOS, AMPK alpha, pAMPKThr172 and mtTFA were determined in PVAT. The contents of adiponectin, leptin and TNF-alpha were evaluated systemically and locally.Key findings: The PVAT+ rings did not modify the relaxing responses to ACh and SNP whereas it showed anticontractile effects for both PHE and 5-HT agents in the SD and TR groups. The amount of PVAT was markedly reduced in TR (3.6 +/- 03 mg/mm) compared with SD (6.8 +/- 0.6 mg/mm). Increased protein expressions of eNOS, pAMPKThr172 and mtTFA were observed in PVAT from TR animals, without modifications in PVAT-derived adiponectin, leptin and TNF-alpha. Circulatory leptin levels were reduced in TR without changes in adiponectin.Significance: Our findings show that exercise training for 8 weeks did not alter the anticontractile effects induced by PVAT in rat-isolated aorta. Moreover, PVAT-derived adipokine, adiponectin and leptin levels were not different in trained healthy animals despite a significant metabolic adaptation and reduction in periaortic adipose tissue amount. (C) 2015 Elsevier Inc. All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

MicroRNA miR-222 mediates pioglitazone beneficial effects on skeletal muscle of diet-induced obese mice

Pioglitazone belongs to the class of drugs thiazolidinediones (TZDs) and is an oral hypoglycemic drug, used in the treatment of type 2 diabetes, which improves insulin sensitivity in target tissues. Adipose tissue is the main target of pioglitazone, a PPARg and PPARa agonist; however, studies also point to skeletal muscle as a target. Non-PPAR targets of TZDs have been described, thus we aimed to study the direct effects of pioglitazone on skeletal muscle and the possible role of microRNAs as targets of this drug. Pioglitazone treatment of obese mice increased insulin-mediated glucose transport as a result of increased fatty acid oxidation and mitochondrial activity. PPARg blockage by treatment with GW9662 nullified pioglitazone's effect on systemic and muscle insulin sensitivity and citrate synthase activity of obese mice. After eight weeks of high-fat diet, miR-221-3p expression in soleus muscle was similar among the groups and miR-23b-3p and miR-222-3p were up-regulated in obese mice compared to the control group, and treatment with pioglitazone was able to reverse this condition. In vitro studies in C2C12 cells suggest that inhibition of miR-222-3p protects C2C12 cells from insulin resistance and increased non-mitochondrial respiration induced by palmitate. Together, these data demonstrate a role of pioglitazone in the downregulation of microRNAs that is not dependent on PPARg. Moreover, miR-222 may be a novel PPARg-independent mechanism through which pioglitazone improves insulin sensitivity in skeletal muscle501COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPsem informaçãosem informaçã

Acute Exercise Improves Insulin Clearance and Increases the Expression of Insulin-Degrading Enzyme in the Liver and Skeletal Muscle of Swiss Mice

<div><p>The effects of exercise on insulin clearance and IDE expression are not yet fully elucidated. Here, we have explored the effect of acute exercise on insulin clearance and IDE expression in lean mice. Male Swiss mice were subjected to a single bout of exercise on a speed/angle controlled treadmill for 3-h at approximately 60–70% of maximum oxygen consumption. As expected, acute exercise reduced glycemia and insulinemia, and increased insulin tolerance. The activity of AMPK-ACC, but not of IR-Akt, pathway was increased in the liver and skeletal muscle of trained mice. In an apparent contrast to the reduced insulinemia, glucose-stimulated insulin secretion was increased in isolated islets of these mice. However, insulin clearance was increased after acute exercise and was accompanied by increased expression of the insulin-degrading enzyme (IDE), in the liver and skeletal muscle. Finally, C2C12, but not HEPG2 cells, incubated at different concentrations of 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) for 3-h, showed increased expression of IDE. In conclusion, acute exercise increases insulin clearance, probably due to an augmentation of IDE expression in the liver and skeletal muscle. The elevated IDE expression, in the skeletal muscle, seems to be mediated by activation of AMPK-ACC pathway, in response to exercise. We believe that the increase in the IDE expression, comprise a safety measure to maintain glycemia at or close to physiological levels, turning physical exercise more effective and safe.</p></div

The MicroRNA miR-696 is regulated by SNARK and reduces mitochondrial activity in mouse skeletal muscle through Pgc1α inhibition

Objective: MicroRNAs (miRNA) are known to regulate the expression of genes involved in several physiological processes including metabolism, mitochondrial biogenesis, proliferation, differentiation, and cell death. Methods: Using “in silico” analyses, we identified 219 unique miRNAs that potentially bind to the 3′UTR region of a critical mitochondrial regulator, the peroxisome proliferator-activated receptor gamma coactivator (PGC) 1 alpha (Pgc1α). Of the 219 candidate miRNAs, miR-696 had one of the highest interactions at the 3′UTR of Pgc1α, suggesting that miR-696 may be involved in the regulation of Pgc1α. Results: Consistent with this hypothesis, we found that miR-696 was highly expressed in the skeletal muscle of STZ-induced diabetic mice and chronic high-fat-fed mice. C2C12 muscle cells exposed to palmitic acid also exhibited a higher expression of miR-696. This increased expression corresponded with a reduced expression of oxidative metabolism genes and reduced mitochondrial respiration. Importantly, reducing miR-696 reversed decreases in mitochondrial activity in response to palmitic acid. Using C2C12 cells treated with the AMP-activated protein kinase (AMPK) activator AICAR and skeletal muscle from AMPKα2 dominant-negative (DN) mice, we found that the signaling mechanism regulating miR-696 did not involve AMPK. In contrast, overexpression of SNF1-AMPK-related kinase (SNARK) in C2C12 cells increased miR-696 transcription while knockdown of SNARK significantly decreased miR-696. Moreover, muscle-specific transgenic mice overexpressing SNARK exhibited a lower expression of Pgc1α, elevated levels of miR-696, and reduced amounts of spontaneous activity. Conclusions: Our findings demonstrate that metabolic stress increases miR-696 expression in skeletal muscle cells, which in turn inhibits Pgc1α, reducing mitochondrial function. SNARK plays a role in this process as a metabolic stress signaling molecule inducing the expression of miR-696

Acute exercise increased AMPK-ACC but not IR-AKT pathway activity.

<p>The p-IR (A) and p-AKT (B) protein levels were unaltered, whereas p-AMPK (C) and p-ACC (D) were increased in the liver, gastrocnemius (GCK) and soleus after a single bout of 3-h exercise on the treadmill. The data are presented as the mean ± S.E.M., n = 4–5. *p≤0.05 <i>vs</i> control.</p

Acute exercise decreased plasma insulin and glucose.

<p>Blood glucose (A) and plasma insulin (B) were reduced in mice after a single bout of 3-h exercise on the treadmill. The data are presented as the mean ± S.E.M., n = 4–5. *p≤0.05 <i>vs</i> control.</p

Acute exercise increased VO₂ without affecting body composition.

<p>Total body weight (A), relative liver weight (B), relative perigonadal fat weight (C) and relative gastrocnemius muscle weight (D) were unaltered in mice after a single bout of 3-h exercise on the treadmill under an increased VO₂ (E). The data are presented as the mean ± S.E.M., n = 3–5. *p≤0.05 <i>vs</i> control.</p