Effects of aging and exercise training on the mechanisms of Angiotensin II-induced vasoconstriction in rat skeletal muscle arterioles

Aging is associated with increases in regional and systemic vascular resistance and impaired ability to increase blood flow to active muscles during exercise. Aging enhances vasoconstrictor responsiveness in both humans and animals, and an increase in Angiotensin II-induced vasoconstriction is one possible mechanism for old age-associated increase in muscle vascular resistance. The purpose of this study was to determine 1) whether aging alters Ang II-induced vasoconstriction, 2) whether exercise training attenuates the age-associated alteration in Ang II-mediated vasoconstriction, and 3) the mechanism(s) through which aging and exercise training alter Ang II-induced vasoconstriction in rat skeletal muscle arterioles. Male Fischer 344 rats were assigned to 4 groups: Young sedentary (YS; 4 months), old sedentary (OS; 24 months), young trained (YT) and old trained (OT). Exercise-trained groups performed treadmill exercises for 60 min/day at 15 m/min, on a 15º incline for 5 days/week for 10-12 weeks. First-order (1A) arterioles were isolated from soleus and gastrocnemius muscles for in vitro experimentation. Intraluminal diameter changes were determined in response to the cumulative addition of Ang II (3×10-11 - 3×10-5 M). Ang II dose responses were then determined following the removal of endothelium and treatment with NG-nitro-L-arginine methyl ester (L-NAME, 10-5 M), a nitric oxide synthase (NOS) inhibitor. Ang II-induced vasoconstriction was augmented in the aged skeletal muscle arterioles, both in soleus and gastrocnemius muscles, and age-associated increases in Ang II-induced vasoconstriction were abolished with the removal of endothelium and with L-NAME. Exercise training ameliorated the age-induced increase in Ang II-vasoconstriction, and this alteration was eliminated by the removal of endothelium and with NOS inhibition. These findings suggest that aging enhances Ang II-induced vasoconstrictor responses in the arterioles from both soleus, high oxidative, and white portion of gastrocnemius, low oxidative glycolytic muscles, and this age-associated change occurs through an endothelium-dependent NOS signaling pathway. These results also demonstrated that exercise training can ameliorate the age-associated increase in Ang II vasoconstriction in the arterioles from both high oxidative and low oxidative glycolytic muscles through an endothelium-mediated NOS mechanism

Korean and American children's evaluations about peer relationships: Friendship, exclusion, and victimization

Korean (N = 398) and U. S. (N = 333) children from 5th and 8th grades were surveyed to investigate how different types of peer rejection (friendship rejection, group exclusion, and peer victimization), and how individualistic (aggression, shyness) and group characteristics (nationality, gender) of the target children of rejection are evaluated by children and adolescents. Children's reasoning was analyzed using a social-cognitive domain model. Culture, age, and gender of participants were key variables in this study. Overall, children and adolescents did not condone the peer rejections, regardless of the gender, grade, and nationality of participants. Victimization elicited the most negative judgments, followed by group exclusion and then friendship. Further, aggression was the most legitimate reason to reject a child, followed by gender of children and then shyness and nationality of children. In victimization contexts, prosocial reasons were predominately used and personal choice reasons were most used in friendship contexts. Children evaluated peer rejection based on group membership traits (gender and nationality) as more unfair than peer rejection based on individual deficit traits (aggression and shyness). Despite the viewpoint that Americans are highly fairness-oriented, Korean participants were more likely to appeal to fairness/discrimination reasoning, while American participants were more likely to appeal to prosocial/empathy and personal choice justifications. When participants believed that the target traits were changeable, they evaluated the rejections as more legitimate and used more group functioning justifications. In addition, when participants experienced more peer rejection, they were more likely to believe that it is wrong to victimize a child, and those who had peer rejection experiences used less stereotypes/group functioning reasoning and more fairness reasoning. The findings contribute to research on peer relationships, moral reasoning, and culture

Effect of Exercise Intervention on Flow-Mediated Dilation in Overweight and Obese Adults: Meta-Analysis

The objective of this meta-analysis is to summarize the effect of exercise intervention on flow-mediated dilatation (FMD) in overweight and obese adults. We searched four electronic databases (PubMed/Medline, Scopus, and CINAHL) through June 2016 for relevant studies pertaining to the effectiveness of exercise intervention on FMD. Seventeen of the 91 studies identified met the inclusion criteria. Comprehensive Meta-Analysis software (version 3) was used to compute the standardized mean difference effect size (ES) and 95% CI using a random effects model. We calculated 34 ESs. We found that exercise intervention had medium and positive effects on FMD, with an overall ES of 0.522 (95% CI = 0.257, 0.786). Heterogeneity of ESs was observed ( = 239, ≤ 0.001, 2 = 86.19), and the effect was moderated by comorbidity ( = 6.39, df = 1, = 0.011). A large ES for the combination exercise, low intensity exercise, and comorbidity subgroups (ES = 0.82∼1.24) was found. We conclude that while exercise intervention significantly improves FMD in overweight and obese adults, the effect may depend on the different characteristics of exercise intervention and on participants’ demographics

Effect of Extracellular Vehicles, Including Exercise Mimetics, for Improving Bone Loss Caused by Osteoblast Endoplasmic Reticulum Stress

PURPOSE This study aims to investigate the bone-muscle crosstalk mechanism by treating dysfunctional osteoblasts with extracellular vehicles (EVs) containing exercise mimetics released during muscle contraction, with the intention of identifying key factors in regulatory mechanisms. METHODS To understand the bone-muscle crosstalk mechanism, the effects of treatment were evaluated in osteoblasts and C2C12. First, palmitate was administered to osteoblasts to induce bone loss due to endoplasmic reticulum (ER) stress. For validation, two groups were evaluated: a control group (CON) and the palmitate treatment group (PAL). Then, C2C12 myotubes were stimulated with electrical pulses to induce muscle contraction, and the released extracellular vehicles (EVs) were harvested and applied to osteoblasts. The results were used to determine the relevant mechanisms for improving bone loss. The impact of EVs released from muscles on osteoblasts was examined using the CD63-GFP plasmid. Four groups were used to compare across the different variables of interest: CON; EV, EV-treated group; PAL; EP, EV+palmitate-treated group. RESULTS The palmitate-treated osteoblasts showed increased expression of inositol-requiring protein 1α (IRE1α), decreased sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA), reduced ER Ca2+, and mitochondrial membrane potential (MMP), indicating induced ER stress. Palmitate-induced ER stress was associated with elevated nuclear factor kappa B (NFκB) and receptor activator of NFκB (RANKL) levels and an increased RANKL/osteoprotegerin (OPG) ratio, causing bone loss. The treatment of osteoblasts with EVs from muscle contraction was found to improve ER stress, the levels of ER Ca2+, MMP, NFκB, and RANKL, and the RANKL/OPG ratio. CONCLUSIONS Palmitate reduces ER Ca2+ and induces osteoblast ER stress while impairing mitochondrial function. Furthermore, through the RANKL/RANK/OPG pathway, a key mechanism related to bone loss is induced. However, substances induced by muscle contraction can act on osteoblasts through exosomes, potentially improving this process

Effects of Acupuncture, Electroacupuncture, and Electrostimulation Treatments on Plantaris by Casting Model

It is essential to seek the therapeutic strategy for attenuating muscle atrophy because muscle atrophy diminishes the quality of life. Acupuncture and electrostimulation have been used as a therapeutic intervention to control pain under pathological conditions. However, little is known about the effects of acupuncture and electrostimulation on skeletal muscle mass and function. PURPOSE: To test whether acupuncture, electroacupuncture, and electrostimulation affect muscle mass and contractile properties METHODS: Forty female Sprague Dawley rats were randomly divided into 5 groups: 1) Control (CON), 2) Cast (CT), 3) CT+ Acupuncture (AC), 4) CT+ Electroacupuncture (EA), and 5) CT+ Electrostimulation (ES) (n=8 each). The plaster casting material was wrapped from the trunk to the middle of one hind paw. Acupuncture and Electro-Acupuncture treatment (2-15 Hz, 2-4 Voltage) was applied by needling ST36 and GB34 (acupoints). Electrostimulation (2-15 Hz, 2-4 Voltage) was conducted by needling in the lateral and medial Gastrocnemius. All treatments were conducted 15 minutes with 3 times/wk for 14 days. Two major atrophy markers, muscle-specific E3 ubiquitin ligases, MAFbx/atrogin1 and muscle ring Finger -1 (MuRF1), were measured using the Western blot method. Data were analyzed using one-way ANOVA with the Least Significant Difference post hoc test. RESULTS: After 2 weeks of casting, plantaris showed significant atrophy in CT compared to the CON group (143.94±13.08 vs. 223.9±20.93 mg; p\u3c0.05). MAFbx/atrogin1 and MuRF1 were significantly increased with CT, while decreased with treatments (AC, EA, and ES). The peak twitch tension was significantly decreased in CT, while increased in AC and ES. However, AC, EA, ES did not alleviate muscle atrophy associated with casting. CONCLUSION: Acupuncture and electrostimulation can be used as effective therapeutic interventions for decreased muscle strength that is associated with casting-induced muscle atrophy

Role of TNF-α in vascular dysfunction

Healthy vascular function is primarily regulated by several factors including EDRF (endothelium-dependent relaxing factor), EDCF (endothelium-dependent contracting factor) and EDHF (endothelium-dependent hyperpolarizing factor). Vascular dysfunction or injury induced by aging, smoking, inflammation, trauma, hyperlipidaemia and hyperglycaemia are among a myriad of risk factors that may contribute to the pathogenesis of many cardiovascular diseases, such as hypertension, diabetes and atherosclerosis. However, the exact mechanisms underlying the impaired vascular activity remain unresolved and there is no current scientific consensus. Accumulating evidence suggests that the inflammatory cytokine TNF (tumour necrosis factor)-α plays a pivotal role in the disruption of macrovascular and microvascular circulation both in vivo and in vitro. AGEs (advanced glycation end-products)/RAGE (receptor for AGEs), LOX-1 [lectin-like oxidized low-density lipoprotein receptor-1) and NF-κB (nuclear factor κB) signalling play key roles in TNF-α expression through an increase in circulating and/or local vascular TNF-α production. The increase in TNF-α expression induces the production of ROS (reactive oxygen species), resulting in endothelial dysfunction in many pathophysiological conditions. Lipid metabolism, dietary supplements and physical activity affect TNF-α expression. The interaction between TNF-α and stem cells is also important in terms of vascular repair or regeneration. Careful scrutiny of these factors may help elucidate the mechanisms that induce vascular dysfunction. The focus of the present review is to summarize recent evidence showing the role of TNF-α in vascular dysfunction in cardiovascular disease. We believe these findings may prompt new directions for targeting inflammation in future therapies

Genetic diversity fuels gene discovery for tobacco and alcohol use

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury(1-4). These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries(5). Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.Peer reviewe

Genetic Drivers of Heterogeneity in Type 2 Diabetes Pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P \u3c 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P &lt; 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p