Cleber R. Alves

Exercise training improves muscle vasodilatation in individuals with T786C polymorphism of endothelial nitric oxide synthase gene.

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 VO(2) 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.

Vascular reactivity and ACE activity response to exercise training are modulated by the +9/−9 bradykinin B2 receptor gene functional polymorphism

The bradykinin receptor B₂ (BDKRB₂) gene +9/-9 polymorphism has been associated with higher gene transcriptional activity, and characteristics of cardiovascular phenotypes and physical performance. We hypothesized that vasodilation and ACE activity response to exercise training is modulated by BDKRB₂ gene. We genotyped 71 healthy volunteers were genotyped for the BDKRB₂ gene polymorphism. Heart rate (HR), mean blood pressure (MBP), and forearm blood flow (FBF) were evaluated. Angiotensin-I converting enzyme (ACE) activity was measured by fluorescence. Aerobic training was performed for 16 wk. All variables were reassessed after completion of the training period. In pretraining period, HR, MBP, FBF, and forearm vascular conductance (FVC) were similar among all genotypes. After physical training, the FBF and the FVC response during handgrip exercise such as area under the curve were higher in -9/-9 carriers than the other two groups. However, there were no changes in HR and MBP for all three groups. In addition, in posttraining period the decrease in ACE activity was higher in the -9/-9 group than the other two groups. These results suggest that reflex muscle vasodilation and ACE activity in response to exercise training are modulated by BDKRB₂ gene +9/-9 polymorphism in healthy individuals.

Influence of angiotensinogen and angiotensin-converting enzyme polymorphisms on cardiac hypertrophy and improvement on maximal aerobic capacity caused by exercise training.

Background The allele threonine (T) of the angiotensinogen has been associated with ventricular hypertrophy in hypertensive patients and soccer players. However, the long-term effect of physical exercise in healthy athletes carrying the T allele remains unknown. We investigated the influence of methionine (M) or T allele of the angiotensinogen and D or I allele of the angiotensin-converting enzyme on left-ventricular mass index (LVMI) and maximal aerobic capacity in young healthy individuals after long-term physical exercise training. Design Prospective clinical trial. Methods Eighty-three policemen aged between 20 and 35 years (mean ± SD 26 ± 4.5 years) were genotyped for the M235T gene angiotensinogen polymorphism (TT, n = 25; MM/MT, n = 58) and angiotensin-converting enzyme gene insertion/deletion (I/D) polymorphism (II, n = 18; DD/DI, n = 65). Left-ventricular morphology was evaluated by echocardiography and maximal aerobic capacity (VO2peak) by cardiopulmonary exercise test before and after 17 weeks of exercise training (50–80% VO2peak). Results Baseline VO2peak and LVMI were similar between TT and MM/MT groups, and II and DD/DI groups. Exercise training increased significantly and similarly VO2peak in homozygous TT and MM/MT individuals, and homozygous II and DD/DI individuals. In addition, exercise training increased significantly LVMI in TT and MM/MT individuals (76.5 ± 3 vs. 86.7 ± 4, P = 0.00001 and 76.2 ± 2 vs. 81.4 ± 2, P = 0.00001, respectively), and II and DD/DI individuals (77.7 ± 4 vs. 81.5 ± 4, P = 0.0001 and 76 ± 2 vs. 83.5 ± 2, P = 0.0001, respectively). However, LVMI in TT individuals was significantly greater than in MM/MT individuals (P = 0.04). LVMI was not different between II and DD/DI individuals. Conclusion Left-ventricular hypertrophy caused by exercise training is exacerbated in homozygous TT individuals with angiotensinogen polymorphism.

Peripheral vascular reactivity and serum BDNF responses to aerobic training are impaired by the BDNF Val66Met polymorphism

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 (V̇o2 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.

Endothelial nitric oxide synthase polymorphisms and adaptation of parasympathetic modulation to exercise training.

PURPOSE There is a large interindividual variation in the parasympathetic adaptation induced by aerobic exercise training, which may be partially attributed to genetic polymorphisms. Therefore, we investigated the association among three polymorphisms in the endothelial nitric oxide gene (-786T>C, 4b4a, and 894G>T), analyzed individually and as haplotypes, and the parasympathetic adaptation induced by exercise training. METHODS Eighty healthy males, age 20-35 yr, were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis, and haplotypes were inferred using the software PHASE 2.1. Autonomic modulation (i.e., HR variability and spontaneous baroreflex sensitivity) and peak oxygen consumption (VO(2peak)) were measured before and after training (running, moderate to severe intensity, three times per week, 60 min·day(-1), during 18 wk). RESULTS Training increased VO(2peak) (P < 0.05) and decreased mean arterial pressure (P < 0.05) in the whole sample. Subjects with the -786C polymorphic allele had a significant reduction in baroreflex sensitivity after training (change: wild type (-786TT) = 2% ± 89% vs polymorphic (-786TC/CC) = -28% ± 60%, median ± quartile range, P = 0.03), and parasympathetic modulation was marginally reduced in subjects with the 894T polymorphic allele (change: wild type (894GG) = 8% ± 67% vs polymorphic (894GT/TT) = -18% ± 59%, median ± quartile range, P = 0.06). Furthermore, parasympathetic modulation percent change was different between the haplotypes containing wild-type alleles (-786T/4b/894G) and polymorphic alleles at positions -786 and 894 (-786C/4b/894T) (-6% ± 56% vs -41% ± 50%, median ± quartile range, P = 0.04). CONCLUSIONS The polymorphic allele at position -786 and the haplotype containing polymorphic alleles at positions -786 and 894 in the endothelial nitric oxide gene were associated with decreased parasympathetic modulation after exercise training.

PBMCs express a transcriptome signature predictor of oxygen uptake responsiveness to endurance exercise training in men

Peripheral blood cells are an accessible environment in which to visualize exercise-induced alterations in global gene expression patterns. We aimed to identify a peripheral blood mononuclear cell (PBMC) signature represented by alterations in gene expression, in response to a standardized endurance exercise training protocol. In addition, we searched for molecular classifiers of the variability in oxygen uptake (V̇o2). Healthy untrained policemen recruits (n = 13, 25 ± 3 yr) were selected. Peak V̇o2 (measured by cardiopulmonary exercise testing) and total RNA from PBMCs were obtained before and after 18 wk of running endurance training (3 times/wk, 60 min). Total RNA was used for whole genome expression analysis using Affymetrix GeneChip Human Gene 1.0 ST. Data were normalized by the robust multiarray average algorithm. Principal component analysis was used to perform correlations between baseline gene expression and V̇o2peak. A set of 211 transcripts was differentially expressed (ANOVA, P < 0.05 and fold change > 1.3). Functional enrichment analysis revealed that transcripts were mainly related to immune function, cell cycle processes, development, and growth. Baseline expression of 98 and 53 transcripts was associated with the absolute and relative V̇o2peak response, respectively, with a strong correlation (r > 0.75, P < 0.01), and this panel was able to classify the 13 individuals according to their potential to improve oxygen uptake. A subset of 10 transcripts represented these signatures to a similar extent. PBMCs reveal a transcriptional signature responsive to endurance training. Additionally, a baseline transcriptional signature was associated with changes in V̇o2peak. Results might illustrate the possibility of obtaining molecular classifiers of endurance capacity changes through a minimally invasive blood sampling procedure.

Signaling Pathways that Mediate Skeletal Muscle Hypertrophy: Effects of Exercise Training

© 2012 Oliveira et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Signaling Pathways that Mediate Skeletal Muscle Hypertrophy: Effects of Exercise Training

Elimination of Influences of the ACTN3 R577X Variant on Oxygen Uptake by Endurance Training in Healthy Individuals

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<2×10(-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.

Anisotropic Brownian motion in ordered phases of DNA fragments

Using Fluorescence Recovery After Photobleaching, we investigate the Brownian motion of DNA rod-like fragments in two distinct anisotropic phases with a local nematic symmetry. The height of the measurement volume ensures the averaging of the anisotropy of the in-plane diffusive motion parallel or perpendicular to the local nematic director in aligned domains. Still, as shown in using a model specifically designed to handle such a situation and predicting a non-Gaussian shape for the bleached spot as fluorescence recovery proceeds, the two distinct diffusion coefficients of the DNA particles can be retrieved from data analysis. In the first system investigated (a ternary DNA-lipid lamellar complex), the magnitude and anisotropy of the diffusion coefficient of the DNA fragments confined by the lipid bilayers are obtained for the first time. In the second, binary DNA-solvent system, the magnitude of the diffusion coefficient is found to decrease markedly as DNA concentration is increased from isotropic to cholesteric phase. In addition, the diffusion coefficient anisotropy measured within cholesteric domains in the phase coexistence region increases with concentration, and eventually reaches a high value in the cholesteric phase.

Aerobic exercise training differentially affects ACE C- and N-domain activities in humans: Interactions with ACE I/D polymorphism and association with vascular reactivity:

Introduction: Previous studies have linked angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism (II, ID and DD) to physical performance. Moreover, ACE has two catalytic domains: NH2 (N) and COOH (C) with distinct functions, and their activity has been found to be modulated by ACE polymorphism. The aim of the present study is to investigate the effects of the interaction between aerobic exercise training (AET) and ACE I/D polymorphism on ACE N- and C-domain activities and vascular reactivity in humans. Materials and methods: A total of 315 pre-selected healthy males were genotyped for II, ID and DD genotypes. Fifty completed the full AET (II, n = 12; ID, n = 25; and DD, n = 13), performed in three 90-minute sessions weekly, in the four-month exercise protocol. Pre- and post-training resting heart rate (HR), peak O2 consumption (VO2 peak), mean blood pressure (MBP), forearm vascular conduction (FVC), total circulating ACE and C- and N-domain activities were assessed. One-way ANOVA and two-way repeated-measures ANOVA were used. Results: In pre-training, all variables were similar among the three genotypes. In post-training, a similar increase in FVC (35%) was observed in the three genotypes. AET increased VO2 peak similarly in II, ID and DD (49±2 vs. 57±1; 48±1 vs. 56±3; and 48±5 vs. 58±2 ml/kg/min, respectively). Moreover, there were no changes in HR and MBP. The DD genotype was also associated with greater ACE and C-domain activities at pre- and post-training when compared to II. AET decreased similarly the total ACE and C-domain activities in all genotypes, while increasing the N-domain activity in the II and DD genotypes. However, interestingly, the measurements of N-domain activity after training indicate a greater activity than the other genotypes. These results suggest that the vasodilation in response to AET may be associated with the decrease in total ACE and C-domain activities, regardless of genotype, and that the increase in N-domain activity is dependent on the DD genotype. Conclusions: AET differentially affects the ACE C- and N-domain activities, and the N-domain activity is dependent on ACE polymorphism.