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In this study, we sought to determine the role of tRNA‐derived fragments in the regulation of gene expression during skeletal muscle cell proliferation and differentiation. We employed cell culture to examine the function of mt‐Ty 5' tiRNAs. Northern blotting, RT‐PCR as well as RNA‐Seq, were performed to determine the effects of mt‐Ty 5' tiRNA loss and gain on gene expression. Standard and transmission electron microscopy (TEM) were used to characterize cell and sub‐cellular structures. mt‐Ty 5'tiRNAs were found to be enriched in mouse skeletal muscle, showing increased levels in later developmental stages. Gapmer‐mediated inhibition of tiRNAs in skeletal muscle C2C12 myoblasts resulted in decreased cell proliferation and myogenic differentiation; consistent with this observation, RNA‐Seq, transcriptome analyses, and RT‐PCR revealed that skeletal muscle cell differentiation and cell proliferation pathways were also downregulated. Conversely, overexpression of mt‐Ty 5'tiRNAs in C2C12 cells led to a reversal of these transcriptional trends. These data reveal that mt‐Ty 5'tiRNAs are enriched in skeletal muscle and play an important role in myoblast proliferation and differentiation. Our study also highlights the potential for the development of tiRNAs as novel therapeutic targets for muscle‐related diseases. [ABSTRACT FROM AUTHOR]

Patients with peripheral artery disease (PAD) have reduced muscle capillary density. Walking training (WT) is recommended for PAD patients. The goal of the study was to verify whether WT promotes angiogenesis in PAD-affected muscle and to investigate the possible role of miRNA-126 and the vascular endothelium growth factor (VEGF) angiogenic pathways on this adaptation. Thirty-two men with PAD were randomly allocated to two groups: WT (n = 16, 2 sessions/week) and control (CO, n = 16). Maximal treadmill tests and gastrocnemius biopsies were performed at baseline and after 12 weeks. Histological and molecular analyses were performed by blinded researchers. Maximal walking capacity increased by 65% with WT. WT increased the gastrocnemius capillary-fiber ratio (WT = 109 ± 13 vs. 164 ± 21 and CO = 100 ± 8 vs. 106 ± 6%, p < 0.001). Muscular expression of miRNA-126 and VEGF increased with WT (WT = 101 ± 13 vs. 130 ± 5 and CO = 100 ± 14 vs. 77 ± 20%, p < 0.001; WT = 103 ± 28 vs. 153 ± 59 and CO = 100 ± 36 vs. 84 ± 41%, p = 0.001, respectively), while expression of PI3KR2 decreased (WT = 97 ± 23 vs. 75 ± 21 and CO = 100 ± 29 vs. 105 ± 39%, p = 0.021). WT promoted angiogenesis in the muscle affected by PAD, and miRNA-126 may have a role in this adaptation by inhibiting PI3KR2, enabling the progression of the VEGF signaling pathway. [ABSTRACT FROM AUTHOR]

Resistance training is accompanied by cardiac hypertrophy, but the role of the renin-angiotensin system (RAS) in this response is elusive. We evaluated this question in 36 male Wistar rats divided into six groups: control (n = 6); trained (n = 6); control + losartan (10 mg * [kg.sup.-1] * [day.sup.-1], n = 6); trained + losartan (n = 6); control + high-salt diet (1%, n = 6); and trained + high-salt diet (1%, n = 6). High salt was used to inhibit the systemic RAS and losartan to block the [AT.sub.1] receptor. The exercise protocol consisted of: 4 x 12 bouts, 5x/wk during 8 wk, with 65-75% of one repetition maximum. Left ventricle weight-to-body weight ratio increased only in trained and trained + high-salt diet groups (8.5% and 10.6%, P < 0.05) compared with control. Also, none of the pathological cardiac hypertrophy markers, atrial natriuretic peptide, and [alpha]MHC (a-myosin heavy chain)to-[beta]MHC ratio, were changed. ACE activity was analyzed by fluorometric assay (systemic and cardiac) and plasma renin activity (PRA) by RIA and remained unchanged upon resistance training, whereas PRA decreased significantly with the high-salt diet. Interestingly, using Western blot analysis and RT-PRC, no changes were observed in cardiac [AT.sub.2] receptor levels, whereas the [AT.sub.1] receptor gene (56%, P < 0.05) and protein (31%, P < 0.05) expressions were upregulated in the trained group. Also, cardiac ANG II concentration evaluated by ELISA remained unchanged (23.27 [+ or -] 2.4 vs. 22.01 [+ or -] 0.8 pg/mg, P > 0.05). Administration of a subhypotensive dose of losartan prevented left ventricle hypertrophy in response to the resistance training. Altogether, we provide evidence that resistance training-induced cardiac hypertrophy is accompanied by induction of [AT.sub.1] receptor expression with no changes in cardiac ANG II, which suggests a local activation of the RAS consistent with the hypertrophic response. [AT.sub.1] receptor; renin-angiotensin system; cardiac hypertrophy; resistance training

Aerobic exercise training (ET) promotes cardiovascular adaptations, including physiological left ventricular hypertrophy (LVH). However, the molecular mechanisms underlying these changes are unclear. The study aimed to elucidate specific microRNAs (miRNAs) and target genes involved with the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling in high-volume ET-induced LVH. Eight-week-old female Wistar rats were assigned to three groups: sedentary control (SC), trained protocol 1 (P1), and trained protocol 2 (P2). P1 consisted of 60 min/day of swimming, 5 times/wk, for 10 wk. P2 consisted of the same protocol as P1 until the 8th week; in the 9th week rats trained 2 times/day, and in the 10th week they trained 3 times/day. Subsequently, structure and molecular parameters were evaluated in the heart. Trained groups demonstrate higher values of peak oxygen uptake (V_ O2peak), exercise tolerance, and LVH in a volume-dependent manner. The miRNA-26a-5p levels were higher in P1 and P2 compared with the SC group (150 ± 15%, d = 1.8; 148 ± 16%, d = 1.7; and 100 ± 7%, respectively; P < 0.05). In contrast, miRNA-16-5p levels were lower in P1 and P2 compared with the SC group (69 ± 5%, d = 2.3, P < 0.01; 37 ± 4%, d = 5.6, P < 0.001; and 100 ± 6%, respectively). Additionally, miRNA-16-5p knockdown and miRNA-26a-5p overexpression significantly promoted cardiomyocyte hypertrophy in neonatal rat cardiomyocytes. Both miRNAs were selected, with the DIANA Tools bioinformatics website, for acting in the mTOR signaling pathway. The protein expression of AKT, MTOR, ribosomal protein S6 kinase beta-1 (P70S6K), and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) were greater in P1 and even more pronounced in P2. Nonetheless, glycogen synthase kinase 3 beta (GSK3β) protein expression was lower in trained groups. Together, these molecular changes may contribute to a pronounced physiological LVH observed in high-volume aerobic training. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to assess the effects of a single bout of maximal walking on blood and muscle nitric oxide (NO) bioavailability, oxidative stress, and inflammation in symptomatic peripheral artery disease (PAD) patients. Methods: A total of 35 men with symptomatic PAD performed a graded maximal exercise test on a treadmill (3.2 km/h, 2% increase in grade every 2 minutes). Plasma samples and gastrocnemius muscle biopsies were collected preexercise and postexercise for assessment of NO bioavailability (plasma NO and muscle, endothelial NO synthase), oxidative stress and antioxidant function (lipid peroxidation [LPO], catalase [CAT], and superoxide dismutase), and inflammation (interleukin-6, C-reactive protein, tumor necrosis factor-α, intercellular adhesion molecules, and vascular adhesion molecules). The effects of the walking exercise were assessed using paired t tests or Wilcoxon tests. Results: After maximal walking, plasma NO and LPO were unchanged (P > .05), plasma CAT decreased, and all blood inflammatory markers increased (all P ≤ .05). In the disease-affected skeletal muscle, endothelial NO synthase, CAT, LPO, and all inflammatory markers increased, whereas superoxide dismutase decreased (all P ≤ .05). Conclusion: In patients with symptomatic PAD, maximal exercise induces local and systemic impairments, which may play a key role in atherogenesis. Exercise strategies that avoid maximal effort may be important to reduce local and systemic damage and enhance clinical benefits. [ABSTRACT FROM AUTHOR]

Aim: To study the relationship between the ACTN3 R577X polymorphism and oxygen uptake (VO2) before and after exercise training. Methods: Police recruits (N = 206, 25 ± 4 y) with RR (n = 75), RX (n = 97), and XX (n = 33) genotypes were selected. After baseline measures, they underwent 18 wk of running endurance training. Peak VO2 was obtained by cardiopulmonary exercise testing. Results: Baseline body weight was not different among genotypes. At baseline, XX individuals displayed higher VO2 at anaerobic threshold, respiratory compensation point, and exercise peak than did RR individuals (P < .003). Endurance training significantly increased VO2 at anaerobic threshold, respiratory compensation point, and exercise peak (P < 2 x 10-6), but the differences between XX and RR were no longer observed. Only relative peak VO2 exercise remained higher in XX than in RR genotype (P = .04). In contrast, the increase in relative peak VO2 was greater in RR than in XX individuals (12% vs 6%; P = .02). Conclusion: ACTN3 R577X polymorphism is associated with VO2. XX individuals have greater aerobic capacity. Endurance training eliminates differences in peak VO2 between XX and RR individuals. These findings suggest a ceiling-effect phenomenon, and, perhaps, trained individuals may not constitute an adequate population to explain associations between phenotypic variability and gene variations. [ABSTRACT FROM AUTHOR]

This study examined the impact of submaximal walking training (WT) on local and systemic nitric oxide (NO) bioavailability, inflammation, and oxidative stress in patients with intermittent claudication (IC). The study employed a randomised, controlled, parallel group design and was performed in a single centre. Thirty-two men with IC were randomly allocated to two groups: WT (n = 16, two sessions/week, 15 cycles of two minutes walking at an intensity corresponding to the heart rate obtained at the pain threshold interspersed by two minutes of upright rest) and control (CO, n = 16, two sessions/week, 30 minutes of stretching). NO bioavailability (blood NO and muscle nitric oxide synthase [eNOS]), redox homeostasis (catalase [CAT], superoxide dismutase [SOD], lipid peroxidation [LPO] measured in blood and muscle), and inflammation (interleukin-6 [IL-6], C-reactive protein [CRP], tumour necrosis factor α [TNF-α], intercellular adhesion molecules [ICAM], vascular adhesion molecules [VCAM] measured in blood and muscle) were assessed at baseline and after 12 weeks. WT statistically significantly increased blood NO, muscle eNOS, blood SOD and CAT, and muscle SOD and abolished the increase in circulating and muscle LPO observed in the CO group. WT decreased blood CRP, ICAM, and VCAM and muscle IL-6 and CRP and eliminated the increase in blood TNF-α and muscle TNF-α, ICAM and VCAM observed in the CO group. WT at an intensity of pain threshold improved NO bioavailability and decreased systemic and local oxidative stress and inflammation in patients with IC. The proposed WT protocol provides physiological adaptations that may contribute to cardiovascular health in these patients. [ABSTRACT FROM AUTHOR]

This study investigated whether regulation of the renin–angiotensin system (RAS) by enalapril and/or aerobic exercise training (AET) causes browning of the subcutaneous white adipose tissue (sWAT). C57BL/6 mice were fed either a standard chow or a high‐fat (HF) diet for 16 weeks. At Week 8, HF‐fed animals were divided into sedentary (HF), enalapril (HF‐E), AET (HF‐T), and enalapril plus AET (HF‐ET) groups. Subsequently, sWAT was extracted for morphometry, determination of RAS expression, and biomarkers of WAT browning. The HF group displayed adipocyte hypertrophy and induction of the classical RAS axis. Conversely, all interventions reduced adiposity and induced the counterregulatory RAS axis. However, only AET raised plasma irisin, increased peroxisome proliferator‐activated receptor‐γ coactivator‐1α, and uncoupling protein‐1 levels, and the expression of PR‐domain containing 16 in sWAT. Therefore, we concluded that AET‐induced sWAT browning was independent of the counterregulatory axis shifting of RAS in HF diet‐induced obesity. [ABSTRACT FROM AUTHOR]

Background: The exercise intolerance in chronic heart failure with reduced ejection fraction (HFrEF) is mostly attributed to alterations in skeletal muscle. However, the mechanisms underlying the skeletal myopathy in patients with HFrEF are not completely understood. We hypothesized that (i) aerobic exercise training (AET) and inspiratory muscle training (IMT) would change skeletal muscle microRNA‐1 expression and downstream‐associated pathways in patients with HFrEF and (ii) AET and IMT would increase leg blood flow (LBF), functional capacity, and quality of life in these patients. Methods: Patients age 35 to 70 years, left ventricular ejection fraction (LVEF) ≤40%, New York Heart Association functional classes II–III, were randomized into control, IMT, and AET groups. Skeletal muscle changes were examined by vastus lateralis biopsy. LBF was measured by venous occlusion plethysmography, functional capacity by cardiopulmonary exercise test, and quality of life by Minnesota Living with Heart Failure Questionnaire. All patients were evaluated at baseline and after 4 months. Results: Thirty‐three patients finished the study protocol: control (n = 10; LVEF = 25 ± 1%; six males), IMT (n = 11; LVEF = 31 ± 2%; three males), and AET (n = 12; LVEF = 26 ± 2%; seven males). AET, but not IMT, increased the expression of microRNA‐1 (P = 0.02; percent changes = 53 ± 17%), decreased the expression of PTEN (P = 0.003; percent changes = −15 ± 0.03%), and tended to increase the p‐AKTser473/AKT ratio (P = 0.06). In addition, AET decreased HDAC4 expression (P = 0.03; percent changes = −40 ± 19%) and upregulated follistatin (P = 0.01; percent changes = 174 ± 58%), MEF2C (P = 0.05; percent changes = 34 ± 15%), and MyoD expression (P = 0.05; percent changes = 47 ± 18%). AET also increased muscle cross‐sectional area (P = 0.01). AET and IMT increased LBF, functional capacity, and quality of life. Further analyses showed a significant correlation between percent changes in microRNA‐1 and percent changes in follistatin mRNA (P = 0.001, rho = 0.58) and between percent changes in follistatin mRNA and percent changes in peak VO2 (P = 0.004, rho = 0.51). Conclusions: AET upregulates microRNA‐1 levels and decreases the protein expression of PTEN, which reduces the inhibitory action on the PI3K‐AKT pathway that regulates the skeletal muscle tropism. The increased levels of microRNA‐1 also decreased HDAC4 and increased MEF2c, MyoD, and follistatin expression, improving skeletal muscle regeneration. These changes associated with the increase in muscle cross‐sectional area and LBF contribute to the attenuation in skeletal myopathy, and the improvement in functional capacity and quality of life in patients with HFrEF. IMT caused no changes in microRNA‐1 and in the downstream‐associated pathway. The increased functional capacity provoked by IMT seems to be associated with amelioration in the respiratory function instead of changes in skeletal muscle. ClinicalTrials.gov (Identifier: NCT01747395) [ABSTRACT FROM AUTHOR]

Background and Aims: The purpose of this study was to investigate whether an intervention with physical activity (PA) would promote positive effects on the angiogenic factors, mobilization, and functionality of circulating endothelial progenitor cells (EPCs) in children with low birth weight (LBW).Methods and Results: Thirty-five children participated in a 10-week PA program (intensity: 75-85% of heart rate reserve, frequency: four times/week, and duration: 45 min). Before and after the PA program, we evaluated anthropometric parameters, blood pressure levels, biochemical profile, number of EPCs, number of EPC colony forming units, and plasma levels of vascular endothelial growth factor-A (VEGF-A), nitric oxide (NO), and matrix metalloproteinases (MMPs) 2 and 9. We found a significant main effect of the PA program on waist circumference (ηp2 = 0.489), cardiorespiratory fitness (ηp2 = 0.463), and MMP-9 (ηp2 = 0.582). Birth weight or the PA program produced significant independent effects on systolic blood pressure (birth weight: ηp2 = 0.431; PA program: ηp2 = 0.615) and EPC colony forming units (birth weight: ηp2 = 0.541; PA program: ηp2 = 0.698) with no significant interactions. The combination of birth weight and the PA program produced a significant interaction effect on the number of circulating EPCs (ηp2 = 0.123), NO (ηp2 = 0.258), and VEGF-A (ηp2 = 0.175). The variation in the number of EPCs from baseline to 10 weeks of the PA program correlated positively with the change in NO (P = 0.002) and VEGF-A (P = 0.004).Conclusions: A 10-week PA program attenuates the adverse effect of LBW on the number and functionality of EPCs; this effect occurs through an improvement in circulating levels of NO and VEGF-A. CLINICAL TRIALS: https://www.clinicaltrials.gov. Unique Identifier: NCT02982967. Date: December/2016. [ABSTRACT FROM AUTHOR]

The present study aimed to test the hypothesis that increased sodium concentration affects the migratory phenotype of vascular smooth muscle cells (VSMCs) independently of the haemodynamic factors. Cell migration was evaluated by wound‐healing assay under the following conditions: high sodium (HS, 160 mM) and control (CT, 140 mM). Cell viability was assessed by annexin V and propidium iodide labeling. Cyclooxygenase‐2 (COX‐2) gene expression was analysed by reverse transcription polymerase chain reaction. ERK1/2 phosphorylation was assessed by western blot. Exposure of VSMCs to HS reduced migration, and AT1R blockade prevented this response. HS increased COX‐2 gene expression, and COX‐2 blockade prevented the reduction in VSMC migration induced by HS. HS also increased ERK1/2 phosphorylation, and ERK1/2 inhibition recovered VSMC migration as well as blocked COX‐2 gene expression. The TXA2 receptor blocker, but not the prostacyclin receptor blocker, prevented the HS‐induced VSMCs migration decrease. HS reduces the migration of VSMCs by increasing COX‐2 gene expression via AT1R‐ERK1/2 phosphorylation. In addition, increased COX‐2 by HS seems to modulate the reduction of VSMCs migration by the TXA2 receptor. [ABSTRACT FROM AUTHOR]

Exercise training not only improves the plasma lipid profile but also reduces risk of developing coronary heart disease. We investigate whether plasma lipids and high density lipoprotein (HDL) metabolism are affected by aerobic training and whether the high‐density lipoprotein cholesterol (HDL‐C) levels at baseline influence exercise‐induced changes in HDL. Seventy‐one male sedentary volunteers were evaluated and allocated in two subgroups, according to the HLD‐C levels (< or >40 mg/dL). Participants underwent an 18‐week aerobic training period. Blood was sampled before and after training for biochemical analysis. Plasma lipids, apolipoproteins, HDL diameter, and VO2 peak were determined. Lipid transfers to HDL were determined in vitro by incubating plasma samples with a donor lipid artificial nanoemulsion. After the 18‐week period of aerobic training, the VO2 peak increased, while the mean body mass index (BMI) decreased. HDL‐C concentration was higher after the training period, but low‐density lipoprotein cholesterol (LDL‐C) and non‐HDL‐C did not change. The transfer of esterified cholesterol and phospholipids was greater after exercise training, but the triacylglycerol and unesterified cholesterol transfers were unchanged. The HDL particle diameter increased after aerobic training in all participants. When the participants were separated in low‐HDL and normal‐HDL groups, the postaerobic exercise increment in HDL‐C was higher in the low‐HDL group, while the transfer of esterified cholesterol was lower. In conclusion, aerobic exercise training increases the lipid transfers to HDL, as measured by an in vitro method, which possibly contributes to the classical elevation of the HDL‐C associated with training. [ABSTRACT FROM AUTHOR]

Hypertension is a difficult disease to control and exercise training plays a key role in hypertension control. Some individuals are not responsive to exercise training, so we highlight the polymorphism of angiotensin I converting enzyme, as a factor responsible for this lack of responsiveness. The aim of this study was to evaluate the influence of ACE (I/D) genotypes on effects of resistance training on blood pressure and chronic inflammation. Eighty-six hypertensive volunteers, aged between 60 and 80, were evaluated. They performed 16 weeks of resistance training at 50% of 1 maximal repetition. The greatest benefits were seen on homozygous of the Insertion allele, whom presented reduction of systolic blood pressure (SBP: 129.31±13.34 vs. 122.56±9.68 mmHg, p<0.001) and diastolic blood pressure (DBP: 79.18±8.05 vs. 70.12±7.71 mmHg, p<0.01) during daytime period, and in 24h period (SBP: 127.12±13.65 vs. 121.06±9.68 mmHg, p<0.001 and DBP: 71.87±8.39 vs. 68.75±8.72 mmHg, p<0.05) and also increased circulating adiponectin levels (4.04±1.79 vs. 6.00±2.81 ng/mL, p<0.01). Other genotypes showed no changes in blood pressure and biochemical parameters. Our results suggest a cardio protective factor of I allele, since only those homozygous showed reductions in blood pressure and increases in adiponectin. [ABSTRACT FROM AUTHOR]

Moderate physical exercise acts at molecular and behavioural levels, such as interfering in neuroplasticity, cell death, neurogenesis, cognition and motor functions. Therefore, the aim of this study is to analyse the cellular effects of moderate treadmill running upon substantia nigra during early neurodegeneration. Aged male Lewis rats (9-month-old) were exposed to rotenone 1mg/kg/day (8 weeks) and 6 weeks of moderate treadmill running, beginning 4 weeks after rotenone exposure. Substantia nigra was extracted and submitted to proteasome and antioxidant enzymes activities, hydrogen peroxide levels and Western blot to evaluate tyrosine hydroxylase (TH), alpha-synuclein, Tom-20, PINK1, TrkB, SLP1, CRMP-2, Rab-27b, LC3II and Beclin-1 level. It was demonstrated that moderate treadmill running, practiced during early neurodegeneration, prevented the increase of alpha-synuclein and maintained the levels of TH unaltered in substantia nigra of aged rats. Physical exercise also stimulated autophagy and prevented impairment of mitophagy, but decreased proteasome activity in rotenone-exposed aged rats. Physical activity also prevented H2O2 increase during early neurodegeneration, although the involved mechanism remains to be elucidated. TrkB levels and its anterograde trafficking seem not to be influenced by moderate treadmill running. In conclusion, moderate physical training could prevent early neurodegeneration in substantia nigra through the improvement of autophagy and mitophagy. [ABSTRACT FROM AUTHOR]

Besides neuronal plasticity, the neurotrophin brain-derived neurotrophic factor (BDNF) is also important in vascular function. The BDNF has been associated with angiogenesis through its specific receptor tropomyosin-related kinase B (TrkB). Additionally, Val66Met polymorphism decreases activity-induced BDNF. Since BDNF and TrkB are expressed in vascular endothelial cells and aerobic exercise training can increase serum BDNF, this study aimed to test the hypotheses: 1) Serum BDNF levels modulate peripheral blood flow; 2) The Val66Met BDNF polymorphism impairs exercise training-induced vasodilation. We genotyped 304 healthy male volunteers (Val66Val, n _221; Val66Met, n = 83) who underwent intense aerobic exercise training on a running track three times/wk for 4 mo. We evaluated pre- and post-exercise training serum BDNF and proBDNF concentration, heart rate (HR), mean blood pressure (MBP), forearm blood flow (FBF), and forearm vascular resistance (FVR). In the pre-exercise training, BDNF, proBDNF, BDNF/proBDNF ratio, FBF, and FVR were similar between genotypes. After exercise training, functional capacity (VO2 peak) increased and HR decreased similarly in both groups. Val66Val, but not Val66Met, increased BDNF (interaction, P = 0.04) and BDNF/proBDNF ratio (interaction, P < 0.001). Interestingly, FBF (interaction, P = 0.04) and the FVR (interaction, P = 0.01) responses during handgrip exercise (HG) improved in Val66Val compared with Val66Met, even with similar responses of HR and MBP. There were association between BDNF/proBDNF ratio and FBF (r = 0.64, P < 0.001) and FVR (r = -0.58, P < 0.001) during HG exercise. These results show that peripheral vascular reactivity and serum BDNF responses to exercise training are impaired by the BDNF Val66Met polymorphism and such responsiveness is associated with serum BDNF concentrations in healthy subjects. [ABSTRACT FROM AUTHOR]

Hypothesis/introduction: Polymorphisms of the angiotensin converting enzyme (ACE) gene can interfere with exercise-induced acute blood pressure (BP) reduction. This cross-over study investigated the acute effect of a single walk on BP and tested whether polymorphisms of the ACE gene might explain the variation in BP responses.Materials and Methods: Thirty-four healthy medicated individuals were randomized to one control and one walking session at 60-75% of heart rate reserve. Subjects left the laboratory wearing an ambulatory BP monitor until waking the next morning.Results: Overall, systolic BP was somewhat lower following the walking session (p=.06), which could be attributed to a consistently lower systolic BP for 5 h after exercise (p-interaction<.04) compared with control rest. Similarly, II/ID individuals had a lower systolic BP (p-interaction=.02) and diastolic BP (p-interaction<.01) for 5 h after walking compared with control rest. Among DD individuals, a single walk did not induce a reduction in BP (p-interaction>.05).Conclusions: Our results showed that postexercise hypotension can occur after a walk at moderate intensity in carriers of the I allele; we were not able to demonstrate this in DD individuals. Our results suggest that genetic variation in the ACE gene might affect the BP response to exercise, although more research is needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Increased oxidative stress and inflammation contribute to impaired walking capacity and endothelial dysfunction in patients with intermittent claudication (IC). The goal of the study was to determine the effects of oral treatment with the antioxidant N-acetylcysteine (NAC) on walking capacity, leg postocclusive reactive hyperemia, circulating levels of inflammatory mediators, and whole blood expression of angiogenic mediators in patients with IC. Following a double-blinded randomized crossover design, 10 patients with IC received NAC (1,800 mg/day for 4 days plus 2,700 mg before the experimental session) and placebo (PLA) before undergoing a graded treadmill exercise test. Leg postocclusive reactive hyperemia was assessed before and after the test. Blood samples were taken before and after NAC or PLA ingestions and 5 and 30 min after the exercise test for the analysis of circulating inflammatory and angiogenic markers. Although NAC increased the plasma ratio of reduced to oxidized glutathione, there were no differences between experimental sessions for walking tolerance and postocclusive reactive hyperemia. Plasma concentrations of soluble vascular cell adhesion protein-1, monocyte chemotactic protein-1, and endothelin-1 increased similarly following maximal exercise after PLA and NAC (P < 0.001). Whole blood expression of pro-angiogenic microRNA-126 increased after maximal exercise in the PLA session, but treatment with NAC prevented this response. Similarly, exercise-induced changes in whole blood expression of VEGF, endothelial nitric oxide synthase and phosphatidylinositol 3-kinase R2 were blunted after NAC. In conclusion, oral NAC does not increase walking tolerance or leg blood flow in patients with IC. In addition, oral NAC prevents maximal exercise-induced increase in the expression of circulating microRNA-126 and other angiogenic mediators in patients with IC. [ABSTRACT FROM AUTHOR]

Left ventricular (LV) hypertrophy is an important physiological compensatory mechanism in response to chronic increase in hemodynamic overload. There are two different forms of LV hypertrophy, one physiological and another pathological. Aerobic exercise induces beneficial physiological LV remodeling. The molecular/cellular mechanisms for this effect are not totally known, and here we review various mechanisms including the role of microRNA (miRNA). Studies in the heart, have identified antihypertrophic miRNA-1, -133, -26, -9, -98, -29, -378, and -145 and prohypertrophic miRNA-143, -103, -130a, -146a, -21, -210, -221, -222, -27a/b, -199a/b, -208, -195, -499, -34a/b/c, -497, -23a, and -15a/b. Four miRNAs are recognized as cardiacspecific: miRNA-1, -133a/b, -208a/b, and -499 and called myomiRs. In our studies we have shown that miRNAs respond to swimming aerobic exercise by 1) decreasing cardiac fibrosis through miRNA-29 increasing and inhibiting collagen, 2) increasing angiogenesis through miRNA-126 by inhibiting negative regulators of the VEGF pathway, and 3) modulating the renin-angiotensin system through the miRNAs-27a/b and -143. Exercise training also increases cardiomyocyte growth and survival by swimming-regulated miRNA-1, -21, -27a/b, -29a/c, -30e, -99b, -100, -124, -126, -133a/b, -143, -144, -145, -208a, and -222 and running-regulated miRNA-1, -26, -27a, -133, -143, -150, and -222, which influence genes associated with the heart remodeling and angiogenesis. We conclude that there is a potential role of these miRNAs in promoting cardioprotective effects on physiological growth. [ABSTRACT FROM AUTHOR]

Previous studies have demon-strated that muscle mechanoreflex and metaboreflex controls are altered in heart failure (HF), which seems to be due to changes in cyclooxygenase (COX) pathway and changes in receptors on afferent neurons, including transient receptor potential vanilloid type-1 (TRPV1) and cannabinoid receptor type-1 (CB1). The purpose of the present study was to test the hypotheses: 1) exercise training (ET) alters the muscle metaboreflex and mechanoreflex control of muscle sympathetic nerve activity (MSNA) in HF patients. 2) The alteration in metaboreflex control is accompanied by increased expression of TRPV1 and CB1 receptors in skeletal muscle. 3) The alteration in mechanoreflex control is accompanied by COX-2 pathway in skeletal muscle. Thirty-four consecutive HF patients with ejection fractions <40% were randomized to untrained (n = 17; 54 ± 2 yr) or exercise-trained (n = 17; 56 ± 2 yr) groups. MSNA was recorded by microneurography. Mechanoreceptors were activated by passive ex-ercise and metaboreceptors by postexercise circulatory arrest (PECA). COX-2 pathway, TRPV1, and CB1 receptors were measured in muscle biopsies. Following ET, resting MSNA was decreased com-pared with untrained group. During PECA (metaboreflex), MSNA responses were increased, which was accompanied by the expression of TRPV1 and CB1 receptors. During passive exercise (mechanore-flex), MSNA responses were decreased, which was accompanied by decreased expression of COX-2, prostaglandin-E2 receptor-4, and thromboxane-A2 receptor and by decreased in muscle inflammation, as indicated by increased miRNA-146 levels and the stable NF-κB/ iκB-α ratio. In conclusion, ET alters muscle metaboreflex and mecha-noreflex control of MSNA in HF patients. This alteration with ET is accompanied by alteration in TRPV1 and CB1 expression and COX-2 pathway and inflammation in skeletal muscle. [ABSTRACT FROM AUTHOR]

Background: Myocardial infarction (MI) is accompanied by cardiac growth, increased collagen deposition, cell death and new vascularization of the cardiac tissue, which results in reduced ventricular compliance. The MiRNA-29 family (29a, 29b, and 29c) targets mRNAs that encode collagens and other proteins involved in fibrosis. In this study we assessed the effects of swimming training (ST) on expression of the cardiac miRNA-29 family and on genes encoding collagen after MI in rats. Methods: ST consisted of 60 min/day/10 weeks and began four weeks after MI. MiRNA and collagen expression analysis were performed in the infarcted region (IR), border region (BR) of the infarcted region and in the remote myocardium (RM) of the left ventricle. Results: MiRNA-29a expression increased 32% in BR and 52% in RM in the TR-INF compared with SED-INF. MiRNA-29c increased by 63% in BR and 55% in RM in TR-INF compared with SED-INF group. COL IAI and COL IIIAI decreased by 63% and 62% in TR-INF, respectively, compared with SED-INF. COLIIIAI expression decreased by 16% in TR-INF compared with SED-INF. Conclusion: Altogether, our results showed that ST restores cardiac miRNA-29 (a and c) levels and prevents COL IAI and COL IIIAI expression in BR and RM, which may contribute to the improvement in ventricular function induced by swimming training, after MI. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Although obesity has been associated with metabolic and cardiac disturbances, the carrier mechanisms for these responses are poorly understood. This study analyzed whether angiotensin II blockade attenuates metabolic and cardiovascular disorders in rats with diet-induced obesity. Material and Methods: Wistar-Kyoto (n = 40) rats were subjected to control (C; 3.2 kcal/g) and hypercaloric diets (OB; 4.6 kcal/g) for 30 weeks. Subsequently, rats were distributed to four groups: C, CL, OB, and OBL. L groups received Losartan (30 mg/kg/day) for five weeks. After this period we performed in vivo glucose tolerance and insulin tolerance tests, and measured triacylglycerol, insulin, angiotensin-converting enzyme activity (ACE), and leptin levels. Cardiovascular analyzes included systolic blood pressure (SBP), echocardiography, myocardial morphometric study, myosin heavy chain composition, and measurements of myocardial protein levels of angiotensin, extracellular signal-regulated (ERK1/2), c-Jun amino-terminal kinases (JNK), insulin receptor subunit β (βIR), and phosphatidylinositol 3-kinase (PI3K) by Western Blot. Results: Glucose metabolism, insulin, lipid, and ACE activity disorders observed with obesity were minimized by Losartan. Moreover, obesity was associated with increased SBP, myocardial hypertrophy, interstitial fibrosis and improved systolic performance; these effects were also minimized with Losartan. On a molecular level, OB exhibited higher ERK, Tyr-phosphorylated βIR, and PI3K expression, and reduced myocardial angiotensin and JNK expression. ERK and JNK expression were regulated in the presence of Losartan, while angiotensin, Tyr-βRI, total and Tyr-phosphorylated PI3K expression were elevated in the OBL group. Conclusion: Angiotensin II blockade with Losartan attenuates obesity-induced metabolic and cardiovascular changes. [ABSTRACT FROM AUTHOR]

The article presents a study on aerobic exercise training and its significance in the prevention and treatment of hypertension. The investigation proves the activity reduces blood pressure, improves vascularization and regulates microRNAs. An overview of the methodology and data analysis is also provided.

Aerobic exercise training leads to a physiological, nonpathological left ventricular hypertrophy; however, the underlying biochemical and molecular mechanisms of physiological left ventricular hypertrophy are unknown. The role of microRNAs regulating the classic and the novel cardiac renin-angiotensin (Ang) system was studied in trained rats assigned to 3 groups: (1) sedentary; (2) swimming trained with protocol 1 (T1, moderate-volume training); and (3) protocol 2 (T2, high-volume training). Cardiac Ang I levels, Ang-converting enzyme (ACE) activity, and protein expression, as well as Ang II levels, were lower in T1 and T2; however, Ang II type 1 receptor mRNA levels (69% in T1 and 99% in T2) and protein expression (240% in T1 and 300% in T2) increased after training. Ang II type 2 receptor mRNA levels (220%) and protein expression (332%) were shown to be increased in T2. In addition, T1 and T2 were shown to increase ACE2 activity and protein expression and Ang (1-7) levels in the heart. Exercise increased microRNA-27a and 27b, targeting ACE and decreasing microRNA-143 targeting ACE2 in the heart. Left ventricular hypertrophy induced by aerobic training involves microRNA regulation and an increase in cardiac Ang II type 1 receptor without the participation of Ang II. Parallel to this, an increase in ACE2, Ang (1-7), and Ang II type 2 receptor in the heart by exercise suggests that this nonclassic cardiac renin-angiotensin system counteracts the classic cardiac renin-angiotensin system. These findings are consistent with a model in which exercise may induce left ventricular hypertrophy, at least in part, altering the expression of specific microRNAs targeting renin-angiotensin system genes. Together these effects might provide the additional aerobic capacity required by the exercised heart. [ABSTRACT FROM AUTHOR]

Allele T at promoter region of the eNOS gene has been associated with an increase in coronary disease mortality, suggesting that this allele increases susceptibility for endothelial dysfunction. In contrast, exercise training improves endothelial function. Thus, we hypothesized that: 1) Muscle vasodilatation during exercise is attenuated in individuals homozygous for allele T, and 2) Exercise training improves muscle vasodilatation in response to exercise for TT genotype individuals. From 133 preselected healthy individuals genotyped for the T786C polymorphism, 72 participated in the study: TT (n = 37; age 27 ± 1 yr) and CT+CC (n = 35; age 26 ± 1 yr). Forearm blood flow (venous occlusion plethysmography) and blood pressure (oscillometric automatic cuff) were evaluated at rest and during 30% handgrip exercise. Exercise training consisted of three sessions per week for 18 wk, with intensity between anaerobic threshold and respiratory compensation point. Resting forearm vascular conductance (FVC, P = 0.17) and mean blood pressure (P = 0.70) were similar between groups. However, FVC responses during handgrip exercise were significantly lower in TT individuals compared with CT+CC individuals (0.39 ± 0.12 vs. 1.08 ± 0.27 units, P = 0.01). Exercise training significantly increased peak VO2 in both groups, but resting FVC remained unchanged. This intervention significantly increased FVC response to handgrip exercise in TT individuals (P = 0.03), but not in CT+CC individuals (P = 0.49), leading to an equivalent FVC response between TT and CT+CC individuals (1.05 ± 0.18 vs. 1.59 ± 0.27 units, P = 0.27). In conclusion, exercise training improves muscle vasodilatation in response to exercise in TT genotype individuals, demonstrating that genetic variants influence the effects of interventions such as exercise training. [ABSTRACT FROM AUTHOR]

Introduction.This study addressed the role of the local renin-angiotensin system (RAS) in the left ventricular hypertrophy (LVH) induced by swimming training using pharmacological blockade.Materials and methods. Female Wistar rats treated with enalapril maleate (60 mg.kg-1.d -1, n=38), losartan (20 mg.kg-1.d-1, n=36) or high salt diet (1% NaCl, n=38) were trained by two protocols (T1: 60-min swimming session, 5 days per week for 10 weeks and T2: the same T1 protocol until the 8th week, then 9th week they trained twice a day and 10th week they trained three times a day). Salt loading prevented activation of the systemic RAS. Haemodynamic parameters, soleus citrate synthase (SCS) activity and LVH (left ventricular/body weight ratio, mg/g) were evaluated.Results. Resting heart rate decreased in all trained groups. SCS activity increased 41% and 106% in T1 andT2 groups, respectively. LVH was 20% and 30% in T1 andT2 groups, respectively. Enalapril prevented 39% of the LVH in T2 group (p<0.05). Losartan prevented 41% in T1 and 50% inT2 (p<0.05) of the LVH in trained groups. Plasma renin activity (PRA) was inhibited in all salt groups and it was increased in T2 group.Conclusions.These data provide evidence that the physiological LVH induced by swimming training is regulated by local RAS independent from the systemic, because the hypertrophic response was maintained even when PRA was inhibited by chronic salt loading. However, other systems can contribute to this process. [ABSTRACT FROM PUBLISHER]

Resistance training is accompanied by cardiac hypertrophy, but the role of the renin-angiotensin system (RAS) in this response is elusive. We evaluated this question in 36 male Wistar rats divided into six groups: control (n = 6); trained (n = 6); control + losartan (10 mg·kg-1·day-1, n = 6); trained + losartan (n = 6); control + high-salt diet (1%, n = 6); and trained + high-salt diet (1%, n 6). High salt was used to inhibit the systemic RAS and losartan to block the AT1 receptor. The exercise protocol consisted of: 4 ×12 bouts, 5×/wk during 8 wk, with 65-75% of one repetition maximum. Left ventricle weight-to-body weight ratio increased only in trained and trained + high-salt diet groups (8.5% and 10.6%, P < 0.05) compared with control. Also, none of the pathological cardiac hypertrophy markers, atrial natriuretic peptide, and αMHC (α-myosin heavy chain)-to-βMHC ratio, were changed. ACE activity was analyzed by fluorometric assay (systemic and cardiac) and plasma renin activity (PRA) by RIA and remained unchanged upon resistance training, whereas PRA decreased significantly with the high-salt diet. Interestingly, using Western blot analysis and RT-PRC, no changes were observed in cardiac AT2 receptor levels, whereas the AT1 receptor gene (56%, P < 0.05) and protein (31%, P < 0.05) expressions were upregulated in the trained group. Also, cardiac ANG II concentration evaluated by ELISA remained unchanged (23.27 ± 2.4 vs. 22.01 ± 0.8 pg/mg, P> 0.05). Administration of a subhypotensive dose of losartan prevented left ventricle hypertrophy in response to the resistance training. Altogether, we provide evidence that resistance training-induced cardiac hypertrophy is accompanied by induction of AT1 receptor expression with no changes in cardiac ANG II, which suggests a local activation of the RAS consistent with the hypertrophic response. [ABSTRACT FROM AUTHOR]

Cardiac hypertrophy is a major mechanism of adaptation of the heart by workload. We evaluate the effect of aerobic exercise training on the miRNAs expression profiling in the heart of spontaneously hypertensive rats (SHR), as well as we selected miRNAs with altered pattern in SHR and reversed by physical training. Also, we analyze their functional role through bioinformatics applications. Male rats were assigned into 3 groups: sedentary hypertensive rats (SHR-S), trained SHR (SHR-T) and sedentary Wistar Kyoto rats (WKY-S). The SHR-T group performed a swimming training protocol of 60 min/5x/week, 1x/day/10 weeks, with 4% caudal body weight workload. We analyzed hemodynamic (blood pressure, BP and resting heart rate, HR), functional (physical capacity, oxygen consumption and echocardiogram), biochemical (349 cardiac microRNAs by microarray and Real Time-PCR to miRNAs) and computational (prediction of targets and annotation cell signaling pathways) parameters. The main findings were: 1. The BP and HR decreased in SHR-T group compared to the SHR-S; 2. The exercise tolerance and VO2 peak increased in SHR-T group; 3.Echocardiographic analysis showed that the E wave, A wave and E/A ratio improved in SHR-T group; 4. Microarray analysis found six different miRNAs expression profile in the comparison groups WKY-S, SHR-S and SHR-T; 5. Six miRNAs were altered in SHR-S and were reversed in the SHR-T (miR-1,22, 27a, 27b, 29c and 451); 7. Bioinformatics analysis showed that this miRNA cluster has multiple predicted targets in signaling pathways related to cardiac remodeling as MAPK, Wnt and TGF-beta and others genes associate to cytoskeletal structure and energetic metabolism.These results suggest that miRNAs: 1, 22, 27a, 27b, 29c and 451 can be controlling cell signaling pathways involved in the process of reversing the disease. These results open new perspectives on the use of these molecules as a therapeutic treatment. [ABSTRACT FROM AUTHOR]