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This update of the human gene map for physical performance and health-related fitness phenotypes covers the research advances reported in 2006 and 2007. The genes and markers with evidence of association or linkage with a performance or a fitness phenotype in sedentary or active people, in responses to acute exercise, or for training-induced adaptations are positioned on the map of all autosomes and sex chromosomes. Negative studies are reviewed, but a gene or a locus must be supported by at least one positive study before being inserted on the map. A brief discussion on the nature of the evidence and on what to look for in assessing human genetic studies of relevance to fitness and performance is offered in the introduction, followed by a review of all studies published in 2006 and 2007. The findings from these new studies are added to the appropriate tables that are designed to serve as the cumulative summary of all publications with positive genetic associations available to date for a given phenotype and study design. The fitness and performance map now includes 214 autosomal gene entries and quantitative trait loci plus seven others on the X chromosome. Moreover, there are 18 mitochondrial genes that have been shown to influence fitness and performance phenotypes. Thus,the map is growing in complexity. Although the map is exhaustive for currently published accounts of genes and exercise associations and linkages, there are undoubtedly many more gene-exercise interaction effects that have not even been considered thus far. Finally, it should be appreciated that most studies reported to date are based on small sample sizes and cannot therefore provide definitive evidence that DNA sequence variants in a given gene are reliably associated with human variation in fitness and performance traits. [ABSTRACT FROM AUTHOR]

Both aberrant vascular reactivity to acute cardiovascular stress and epigenetic mechanisms such as microRNA (miR) may underlie the increased propensity for African Americans (AA) to develop cardiovascular disease. This study assessed racial differences in acute induced endothelial inflammation and related miRs. Cultured human umbilical vein endothelial cells (HUVECs) derived from AA and Caucasian Americans (CA) were exposed to influenza vaccine to determine changes in inflammatory markers, endothelial nitric oxide synthase (eNOS), and miR expression/release. Endothelial function [flow-mediated dilation (FMD)], circulating IL-6, and circulating miR were also measured in young, healthy AA and CA individuals before and after receiving the influenza vaccine. There were no significant racial differences in any parameters at baseline. The vaccine induced increases in IL-6 release (24%, P = 0.02) and ICAM-1 mRNA (40%, P = 0.03), as well as reduced eNOS mRNA (24%, P = 0.04) in AA HUVECs, but not in CA HUVECs (all P > 0.05). Intracellular levels of anti-inflammatory miR-221-3p and miR-222-3p increased specifically in CA HUVECs (72% and 53%, P = 0.04 and P = 0.06), whereas others did not change in either race. HUVEC secretion of several miRs decreased in both races, whereas the release of anti-inflammatory miR-150-5p was decreased only by AA cells (-30%, P = 0.03). In individuals of both races, circulating IL-6 increased approximately twofold 24 h after vaccination (both P < 0.01) and returned to baseline levels by 48 h, whereas FMD remained unchanged. Although macrovascular function was unaffected by acute inflammation in AA and CA individuals, AA endothelial cells exhibited increased susceptibility to acute inflammation and unique changes in related miR. NEW & NOTEWORTHY Used as an acute inflammatory stimulus, the influenza vaccine induced an inflammatory response and decreased eNOS gene expression in endothelial cells derived from African Americans, but not Caucasian Americans. Race-specific changes in intracellular expression and release of specific microRNAs also occurred and may contribute to an exaggerated inflammatory response in African Americans. In vivo, the vaccine caused similar systemic inflammation but had no effect on endothelial function or circulating microRNAs in individuals of either race.

Mechanisms underlying the protective effects of both habitual endurance exercise and the female sex on vascular function are incompletely understood. Blood-borne circulating factors, such as circulating microRNAs (ci-miRs), may partially explain these effects. Blood samples were obtained from young, healthy men and women who either habitually performed endurance exercise (endurance trained) or were relatively inactive (sedentary). Women were tested during the early follicular phase of the menstrual cycle or the placebo pill phase of oral contraceptive to control for estrogen. Cultured human umbilical vein endothelial cells (HUVECs) were exposed to participants' serum in migration, proliferation, and reactive oxygen species (ROS) assays. Real-time quantitative polymerase chain reaction was used to quantify an initial array of 84 cardiovascular disease (CVD)-related ci-miRs, followed by validation of 10 ci-miRs. All participants were devoid of traditional CVD risk factors, and circulating estradiol concentration was not different between groups. Serum of endurance-trained women induced greater HUVEC migration compared with serum of sedentary women. HUVEC ROS production was greater in response to serum of sedentary men compared with serum of endurance-trained men and sedentary women. There were sex effects on the levels of nine ci-miRs, with greater levels in men, while ci-miRs-140-5p and 145-5p were also higher in sedentary compared with endurance-trained men and/or women. In a sex-specific manner, habitual endurance exercise was associated with beneficial effects of serum on HUVECs. Thus, alterations in circulating factors may contribute to the protective effects of habitual endurance exercise on vascular health. Additionally, sex had a greater impact than habitual activity level on the levels of vascular-related ci-miRs. NEW & NOTEWORTHY Serum from sedentary women caused impaired endothelial migration, whereas serum from sedentary men elicited increased endothelial reactive oxygen species production as compared with serum from their endurance-trained counterparts. Select CVD-related circulating microRNAs (ci-miRs) were higher in men than women, while ci-miRs-140-5p and 145-5p were also higher in sedentary versus trained men and/or women. Our data suggest that alterations in circulating factors may contribute to the protective effects of habitual exercise and sex on vascular health.

Concentrations of different circulating microparticles (MPs) may have clinical and physiological relevance to cardiovascular disease pathologies., Purpose: To quantify plasma concentrations of CD31+/CD42b-, CD62E+, and CD34+ MPs across healthy individuals and those with coronary artery disease (CAD) or acute cardiovascular events (non-ST elevation myocardial infarction (NSTEMI)). Fasted blood was obtained from CAD patients (n = 10), NSTEMI patients (n = 13), and healthy older men (n = 15) 60-75 years old., Methods: CD31+/CD42b-, CD62E+, and CD34+ MPs were isolated from plasma and quantified using flow cytometry. Relationships between MP subtypes, fasting blood lipids, blood glucose, blood pressure, body mass index, and total number of medications were assessed., Results: Concentrations of CD31+/CD42b- MPs were significantly lower in CAD and NSTEMI subjects compared with healthy individuals (p = .02 and .003, respectively). No differences between groups were found for CD62E+ or CD34+ MPs (p > .05 for both). Surprisingly, among all variables assessed, only CD62E+ MP concentrations were positively correlated with triglyceride levels (p = .012) and inversely correlated with SBP (p = .03)., Conclusions: Our findings provide support for the use of different MP subtypes, specifically CD31+/CD42b- MPs, as a potential biomarker of cardiovascular disease. Importantly, results from this study should be looked at in adjunct to previous MP work in CVD conditions as a way of highlighting the complex interactions of variables such as comorbid conditions and medications on MP concentrations., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

In 2005 the scientific misconduct case of a noted researcher concluded with, among other things, the retraction of 10 papers. However, these articles continue to be cited at relatively high rates. The objectives of this paper are: 1 ) to track the retraction process of these papers, 2 ) to assess the impact of retraction on subsequent citation rates of these papers, and 3 ) to compare the citation history of these retracted articles and five other high-profile retraction cases. For objective 1 , all five articles to be retracted were retracted and of the four to be corrected, two were retracted and two were corrected. Eight PubMed and journal sites were identified where retraction messages could be conveyed; the number of retraction messages averaged 3.4 ± 2.5 for these nine articles. For objective 2 , an absolute "cleansing" did not occur. While it initially appears there was a relative "cleansing," as citation rates for these articles did decrease after retraction, the reductions in citation rates for these articles (-28%) were the same as those for matched nonretracted publications both by the same author (-28%) and by another investigator (-29%) over the same time frame. Relative to objective 3 , the results for this case are quite different from the five other cases assessing this issue, perhaps because of this investigator's "citation inertia" as a result of the small percentage of his papers that were retracted and the large number of citations to the articles before their retraction and to all of his published articles. NEW & NOTEWORTHY The scientific misconduct and fraud case of a noted exercise physiology researcher was concluded ~15 yr ago, and one the of the results was the retraction of 10 published manuscripts. However, based on a number of comparisons to that same author's and another investigator's citation histories for similar articles, the citation histories for these retracted articles appear to not have been affected whatsoever in the subsequent 15 yr.

High-intensity interval (HII) exercise elicits distinct vascular responses compared to a matched dose of moderate intensity continuous (MOD) exercise. However, the acute effects of HII compared to MOD exercise on arterial stiffness are incompletely understood. Circulating microRNAs (ci-miRs) may contribute to the vascular effects of exercise. We sought to determine exercise intensity-dependent changes in ci-miR potentially underlying changes in arterial stiffness. Ten young, healthy men underwent well-matched, 30-min HII and MOD exercise bouts. RT-qPCR was used to determine the levels of seven vascular-related ci-miRs in serum obtained immediately before and after exercise. Arterial stiffness measures including carotid to femoral pulse wave velocity (cf-PWV), carotid arterial compliance and β-stiffness, and augmentation index (AIx and AIx75) were taken before, 10min after and 60min after exercise. Ci-miR-21-5p, 126-3p, 126-5p, 150-5p, 155-5p, and 181b-5p increased after HII exercise (p < .05), while ci-miR-150-5p and 221-3p increased after MOD exercise (p = .03 and 0.056). One hour after HII exercise, cf-PWV trended toward being lower compared to baseline (p = .056) and was significantly lower compared to 60min after MOD exercise (p = .04). Carotid arterial compliance was increased 60min after HII exercise (p = .049) and was greater than 60min after MOD exercise (p = .02). AIx75 increased 10 min after both HII and MOD exercise (p < .05). There were significant correlations between some of the exercise-induced changes in individual ci-miRs and changes in cf-PWV and AIx/AIx75. These results support the hypotheses that arterial stiffness and ci-miRs are altered in an exercise intensity-dependent manner, and ci-miRs may contribute to changes in arterial stiffness., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Endothelial function typically exhibits a hormetic response to exercise. It is unknown whether endothelial damage occurs in response to acute exercise and could be a contributing mechanism. We sought to determine the effects of acute exercise on endothelial-derived circulating factors proposed to reflect endothelial integrity and activation. Young, healthy men ( n = 10) underwent 30-min moderate continuous (MOD) and high-intensity interval (HII) cycling exercise bouts. Venous blood samples were taken immediately before and after exercise for quantification of circulating endothelial cells (CECs), circulating angiogenic cells (CACs), apoptotic and activated endothelial microvesicles (EMVs), thrombomodulin (TM), von Willebrand factor (vWF), syndecan-1, and circulating microRNAs (ci-miRs) 126-3p and 126-5p. Endothelial function was assessed by flow-mediated dilation (FMD) of the brachial artery before, 10 min after, and 60 min after exercise. Numbers of CECs and EMVs were unchanged by either exercise bout ( P > 0.05). Numbers of all measured CAC subtypes decreased in response to MOD (21%-34%, P < 0.05), whereas only CD31 + /34 + /45 dim/- CACs decreased following HII (21%, P < 0.05). TM and syndecan-1 increased with both exercise intensities (both ~20%, P < 0.05). HII, but not MOD, increased vWF (88%, P < 0.001), ci-miR-126-3p (92%, P = 0.009) and ci-miR-126-5p (110%, P = 0.01). The changes in several circulating factors correlated with changes in FMD following either one or both intensities. Changes in circulating factors do not support the concept of exercise-induced endothelial cell denudation, apoptosis, or activation, though slight disruption of endothelial glycocalyx and membrane integrity may occur. A related loss of mechanotransduction along with mechanisms underlying endothelial activation and ci-miR-126 secretion may relate to changes in endothelial function. NEW & NOTEWORTHY Using circulating endothelial-derived factors, we show that endothelial denudation, apoptosis, and activation do not appear to increase, whereas disrupted endothelial glycocalyx and membrane integrity may occur during both high-intensity interval and moderate intensity cycling. Increases in factors nonspecific to endothelial damage, including von Willebrand factor and microRNA-126, occurred only after high-intensity interval exercise. These results shed light on the hypothesis that disrupted endothelial integrity contributes to the endothelial function response to exercise.

John O. Holloszy, as perhaps the world's preeminent exercise biochemist/physiologist, published >400 papers over his 50+ year career, and they have been cited >41,000 times. In 1965 Holloszy showed for the first time that exercise training in rodents resulted in a doubling of skeletal muscle mitochondria, ushering in a very active era of skeletal muscle plasticity research. He subsequently went on to describe the consequences of and the mechanisms underlying these adaptations. Holloszy was first to show that muscle contractions increase muscle glucose transport independent of insulin, and he studied the mechanisms underlying this response throughout his career. He published important papers assessing the impact of training on glucose and insulin metabolism in healthy and diseased humans. Holloszy was at the forefront of rodent studies of caloric restriction and longevity in the 1980s, following these studies with important cross-sectional and longitudinal caloric restriction studies in humans. Holloszy was influential in the discipline of cardiovascular physiology, showing that older healthy and diseased populations could still elicit beneficial cardiovascular adaptations with exercise training. Holloszy and his group made important contributions to exercise physiology on the effects of training on numerous metabolic, hormonal, and cardiovascular adaptations. Holloszy's outstanding productivity was made possible by his mentoring of ~100 postdoctoral fellows and substantial NIH grant funding over his entire career. Many of these fellows have also played critical roles in the exercise physiology/biochemistry discipline. Thus it is clear that exercise biochemistry and physiology will be influenced by John Holloszy for numerous years to come.

Postmenopausal African American women are at elevated risk for metabolic syndrome (MetS), which predisposes them to cardiovascular disease and other chronic diseases. Circulating microRNAs (ci-miR) are potential mediators of cardiometabolic diseases also impacted by cardiorespiratory fitness (CRF) level. Using real-time quantitative PCR, we compared the expression of vascular-related ci-miRs (miR-21-5p, miR-92a-3p, miR-126-5p, miR-146a-5p, miR-150-5p, miR-221-3p) in sedentary, overweight/obese, postmenopausal African American women based on 1) presence (n = 31) or absence (n = 42) of MetS and 2) CRF level (VO 2peak ) (Very Low < 18.0 mL·kg -1 ·min -1 [n = 31], Low = 18.0-22.0 mL·kg -1 ·min -1 [n = 24], or Moderate >22.0 mL·kg -1 ·min -1 [n = 18]). Endothelial migration rate in response to subjects' serum was assessed to determine the effect of circulating blood-borne factors on endothelial repair. Ci-miR-21-5p was the only ci-miR that differed between women with MetS compared to those without MetS (0.93 ± 0.43 vs. 1.28 ± 0.71, P = 0.03). There were borderline significant differences (P = 0.06-0.09) in ci-miR-21-5p, 126-5p, and 221-3p levels between the CRF groups, and these three ci-miRs correlated with VO 2peak (r = -0.25 to -0.28, P < 0.05). Endothelial migration rate was impaired in response to serum from women with MetS compared to those without after 16-24 h. Serum from women with Moderate CRF induced greater endothelial migration than the Very Low and Low CRF groups after 4 and 16-24 h, that was also not different from a young, healthy reference group. Ci-miR-21-5p is lower in postmenopausal African American women with MetS, while ci-miRs-21-5p, 126-5p, and 221-3p are associated with CRF. Factors which impair endothelial cell migration rate are present in serum of women with MetS, though having Moderate CRF may be protective., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

MicroRNAs (miRNAs) are short, noncoding RNAs that influence biological processes by regulating gene expression after transcription. It was recently discovered that miRNAs are released into the circulation (ci-miRNAs) where they are highly stable and can act as intercellular messengers to affect physiological processes. This review provides a comprehensive summary of the studies to date that have investigated the effects of acute exercise and exercise training on ci-miRNAs in humans. Findings indicate that specific ci-miRNAs are altered in response to different protocols of acute and chronic exercise in both healthy and diseased populations. In some cases, altered ci-miRNAs correlate with fitness and health parameters, suggesting causal mechanisms by which ci-miRNAs may facilitate adaptations to exercise training. However, strong data supporting such mechanisms are lacking. Thus, a purpose of this review is to guide future studies by discussing current and novel proposed roles for ci-miRNAs in adaptations to exercise training. In addition, substantial, fundamental gaps in the field need to be addressed. The ultimate goal of this research is that an understanding of the roles of ci-miRNAs in physiological adaptations to exercise training will one day translate to therapeutic interventions., (Copyright © 2017 the American Physiological Society.)

Paracrine function of circulating angiogenic cells (CACs) is thought to contribute to vascular maintenance. We previously identified S100A8 and S100A9 secreted from physically inactive individuals' CD34 - /CD31 + CACs as negative regulators of capillary-like network formation. The purpose of this study was to investigate further the extremes of the continuum of CAC paracrine actions using two distinctly different groups representing "healthy" and "impaired" CAC function. We aimed to determine how capillary-like network formation in human umbilical vein endothelial cells (HUVECs) is affected by S100A8 and S100A9 in concentrations secreted by CACs from different ends of the health spectrum. CD34 - /CD31 + CACs were isolated and cultured from 10 impaired function individuals defined as older (50-89 yr), non-ST-elevation myocardial infarction patients and 10 healthy individuals defined as younger (18-35 yr), healthy individuals, and conditioned media (CM) was generated. CM from the impaired function group's CACs significantly diminished network formation compared with CM from the healthy group (P < 0.05). We identified elevations in S100A8, S100A9, and S100A8/A9 in the CM from the impaired function group (P < 0.05). Pretreatment of HUVECs with inhibitors to a known S100A8 and S100A9 receptor, Toll-like receptor 4 (TLR4), but not receptor for advanced glycation end products, improved HUVEC network formation (P < 0.05) compared with CM alone in the impaired function conditions. Exposure of HUVECs to the TLR4 signaling inhibitor also blocked recombinant S100A8- and S100A9-mediated reductions in network formation. Collectively, the results suggest that the mechanisms behind impaired CAC CD34 - /CD31 + CM-mediated reductions in capillary-like network formation involve secretion of S100A8 and S100A9 and binding of these proteins to TLR4 receptors on HUVECs., New & Noteworthy: S100A8 and S100A9 proteins in concentrations secreted by CD34 - /CD31 + circulating angiogenic cells (CACs) with impaired function reduce endothelial cell capillary-like network formation. These effects appear to be mediated by Toll-like receptor 4 and are absent with S100A8 and S100A9 in concentrations secreted by healthy CD34 - /CD31 + CACs., (Copyright © 2017 the American Physiological Society.)

While endurance exercise training improves cerebrovascular health and has neurotrophic effects within the hippocampus, the effects of stopping this exercise on the brain remain unclear. Our aim was to measure the effects of 10 days of detraining on resting cerebral blood flow (rCBF) in gray matter and the hippocampus in healthy and physically fit older adults. We hypothesized that rCBF would decrease in the hippocampus after a 10-day cessation of exercise training. Twelve master athletes, defined as older adults (age ≥ 50 years) with long-term endurance training histories (≥15 years), were recruited from local running clubs. After screening, eligible participants were asked to cease all training and vigorous physical activity for 10 consecutive days. Before and immediately after the exercise cessation period, rCBF was measured with perfusion-weighted MRI. A voxel-wise analysis was used in gray matter, and the hippocampus was selected a priori as a structurally defined region of interest (ROI), to detect rCBF changes over time. Resting CBF significantly decreased in eight gray matter brain regions. These regions included: (L) inferior temporal gyrus, fusiform gyrus, inferior parietal lobule, (R) cerebellar tonsil, lingual gyrus, precuneus, and bilateral cerebellum (FWE p < 0.05). Additionally, rCBF within the left and right hippocampus significantly decreased after 10 days of no exercise training. These findings suggest that the cerebrovascular system, including the regulation of resting hippocampal blood flow, is responsive to short-term decreases in exercise training among master athletes. Cessation of exercise training among physically fit individuals may provide a novel method to assess the effects of acute exercise and exercise training on brain function in older adults.

We aimed to determine if chronic endurance-exercise habits affected redox status and paracrine function of CD34(+) and CD34(-)/CD31(+) circulating angiogenic cells (CACs). Subjects were healthy, nonsmoking men and women aged 18-35 yr and categorized by chronic physical activity habits. Blood was drawn from each subject for isolation and culture of CD34(+) and CD34(-)/CD31(+) CACs. No differences in redox status were found in any group across either cell type. Conditioned media (CM) was generated from the cultured CACs and used in an in vitro human umbilical vein endothelial cell-based tube assay. CM from CD34(+) cells from inactive individuals resulted in tube structures that were 29% shorter in length (P < 0.05) and 45% less complex (P < 0.05) than the endurance-trained group. CD34(-)/CD31(+) CM from inactive subjects resulted in tube structures that were 26% shorter in length (P < 0.05) and 42% less complex (P < 0.05) than endurance-trained individuals. Proteomics analyses identified S100A8 and S100A9 in the CM. S100A9 levels were 103% higher (P < 0.05) and S100A8 was 97% higher in the CD34(-)/CD31(+) CM of inactive subjects compared with their endurance-trained counterparts with no significant differences in either protein in the CM of CD34(+) CACs as a function of training status. Recombinant S100A8/A9 treatment at concentrations detected in inactive subjects' CD34(-)/CD31(+) CAC CM also reduced tube formation (P < 0.05). These findings are the first, to our knowledge, to demonstrate a differential paracrine role in CD34(+) and CD34(-)/CD31(+) CACs on tube formation as a function of chronic physical activity habits and identifies a differential secretion of S100A9 by CD34(-)/CD31(+) CACs due to habitual exercise., (Copyright © 2015 the American Physiological Society.)

This is the annual review of the exercise genomics literature in which we report on the highest quality papers published in 2014. We identified a number of noteworthy papers across a number of fields. In 70-89 yr olds, only 19% of angiotensin-converting enzyme (ACE) II homozygotes exhibited significant improvement in gait speed in response to a yearlong physical activity program compared to 30% of ACE D-allele carriers. New studies continue to support the notion that the genetic susceptibility to obesity, as evidenced by a genomic risk score (GRS; based on multiple single nucleotide polymorphisms), is attenuated by 40%-50% in individuals who are physically active, compared to those who are sedentary. One study reported that the polygenic risk for hypertriglyceridemia was reduced by 30%-40% in individuals with high cardiorespiratory fitness. One report showed that there was a significant interaction of a type 2 diabetes GRS with physical activity, with active individuals having the lowest risk of developing diabetes. The protective effect of physical activity was most pronounced in the low GRS tertile (hazard ratio, 0.82). The interaction observed with the diabetes GRS seemed to be dependent on a genetic susceptibility to insulin resistance and not insulin secretion. A significant interaction between PPARα sequence variants and physical activity levels on cardiometabolic risk was observed, with higher activity levels associated with lower risk only in carriers of specific genotypes and haplotypes. The review concludes with a discussion of the importance of replication studies when very large population or intervention discovery studies are not feasible or are cost prohibitive.

The most significant and scientifically sound articles in exercise genomics that were published in 2013 are reviewed in this report. No article on the genetic basis of sedentary behavior or physical activity level was identified. A calcineurin- and alpha actinin-2-based mechanism has been identified as the potential molecular basis for the observed lower muscular strength and power in alpha actinin-3-deficient individuals. Although baseline muscle transcriptomic signatures were found to be associated with strength training-induced muscle hypertrophy, no predictive genomic variants could be identified as of yet. One study found no clear evidence that the inverse relation between physical activity level and incident CHD events was influenced by 58 genomic variants clustered into four genetic scores. Lower physical activity level in North American populations may be driving the apparent risk of obesity in fat mass- and obesity-associated gene (FTO)-susceptible individuals compared with more active populations. Two large studies revealed that common genetic variants associated with baseline levels of plasma HDL cholesterol and triglycerides are not clear predictors of changes induced by interventions focused on weight loss, diet, and physical activity behavior. One large study from Japan reported that a higher fitness level attenuated the arterial stiffness-promoting effect of the Ala54 allele at the fatty acid binding protein 2 locus, which is a controversial finding because previous studies have suggested that Thr54 was the risk allele. Using transcriptomics to generate genomic targets in an unbiased manner for subsequent DNA sequence variants studies appears to be a growing trend. Moreover, exercise genomics is rapidly embracing gene and pathway analysis to better define the underlying biology and provide a foundation for the study of human variation.

High-fat meal consumption alters the circulating cytokine profile and contributes to cardiometabolic diseases. A prior bout of exercise can ameliorate the triglyceride response to a high-fat meal, but the interactive effects of exercise and high-fat meals on cytokines that mediate cardiometabolic risk are not fully understood. We investigated the effects of prior exercise on the responses of circulating tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-8, leptin, retinol-binding protein 4 (RBP4), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), placental growth factor (PlGF), and soluble fms-like tyrosine kinase-1 (sFlt-1) to a high-fat meal. Ten healthy men were studied before and 4 h after ingestion of a high-fat meal either with or without ∼50 min of endurance exercise at 70% of VO2 max on the preceding day. In response to the high-fat meal, lower leptin and higher VEGF, bFGF, IL-6, and IL-8 concentrations were evident (P < 0.05 for all). There was no effect of the high-fat meal on PlGF, TNF-α, or RBP4 concentrations. We found lower leptin concentrations with prior exercise (P < 0.05) and interactive effects of prior exercise and the high-fat meal on sFlt-1 (P < 0.05). The high-fat meal increased IL-6 by 59% without prior exercise and 218% with prior exercise (P < 0.05). In conclusion, a prior bout of endurance exercise does not affect all high-fat meal-induced changes in circulating cytokines, but does affect fasting or postprandial concentrations of IL-6, leptin, and sFlt-1. These data may reflect a salutary effect of prior exercise on metabolic responses to a high-fat meal.

A small number of excellent articles on exercise genomics issues were published in 2012. A new PYGM knock-in mouse model will provide opportunities to investigate the exercise intolerance and very low activity level of people with McArdle disease. New reports on variants in ACTN3 and ACE have increased the level of uncertainty regarding their true role in skeletal muscle metabolism and strength traits. The evidence continues to accumulate on the positive effects of regular physical activity on body mass index or adiposity in individuals at risk of obesity as assessed by their FTO genotype or by the number of risk alleles they carry at multiple obesity-susceptibility loci. The serum levels of triglycerides and the risk of hypertriglyceridemia were shown to be influenced by the interactions between a single nucleotide polymorphism (SNP) in the NOS3 gene and physical activity level. Allelic variation at nine SNPs was shown to account for the heritable component of the changes in submaximal exercise heart rate induced by the HERITAGE Family Study exercise program. SNPs at the RBPMS, YWHAQ, and CREB1 loci were found to be particularly strong predictors of the changes in submaximal exercise heart rate. The 2012 review ends with comments on the importance of relying more on experimental data, the urgency of identifying panels of genomic predictors of the response to regular exercise and particularly of adverse responses, and the exciting opportunities offered by recent advances in our understanding of the global architecture of the human genome as reported by the Encyclopedia of DNA Elements project.

This review of the exercise genomics literature emphasizes the highest quality articles published in 2011. Given this emphasis on the best publications, only a small number of published articles are reviewed. One study found that physical activity levels were significantly lower in patients with mitochondrial DNA mutations compared with controls. A two-stage fine-mapping follow-up of a previous linkage peak found strong associations between sequence variation in the activin A receptor, type-1B (ACVRIB) gene and knee extensor strength, with rs2854464 emerging as the most promising candidate polymorphism. The association of higher muscular strength with the rs2854464 A allele was confirmed in two separate cohorts. A study using a combination of transcriptomic and genomic data identified a comprehensive map of the transcriptomic features important for aerobic exercise training-induced improvements in maximal oxygen consumption, but no genetic variants derived from candidate transcripts were associated with trainability. A large-scale de novo meta-analysis confirmed that the effect of sequence variation in the fat mass and obesity-associated (FTO) gene on the risk of obesity differs between sedentary and physically active adults. Evidence for gene-physical activity interactions on type 2 diabetes risk was found in two separate studies. A large study of women found that physical activity modified the effect of polymorphisms in the lipoprotein lipase (LPL), hepatic lipase (LIPC), and cholesteryl ester transfer protein (CETP) genes, identified in previous genome-wide association study reports, on HDL cholesterol. We conclude that a strong exercise genomics corpus of evidence would not only translate into powerful genomic predictors but also have a major effect on exercise biology and exercise behavior research.

Background: Individuals differ in the response to regular exercise. Whether there are people who experience adverse changes in cardiovascular and diabetes risk factors has never been addressed., Methodology/principal Findings: An adverse response is defined as an exercise-induced change that worsens a risk factor beyond measurement error and expected day-to-day variation. Sixty subjects were measured three times over a period of three weeks, and variation in resting systolic blood pressure (SBP) and in fasting plasma HDL-cholesterol (HDL-C), triglycerides (TG), and insulin (FI) was quantified. The technical error (TE) defined as the within-subject standard deviation derived from these measurements was computed. An adverse response for a given risk factor was defined as a change that was at least two TEs away from no change but in an adverse direction. Thus an adverse response was recorded if an increase reached 10 mm Hg or more for SBP, 0.42 mmol/L or more for TG, or 24 pmol/L or more for FI or if a decrease reached 0.12 mmol/L or more for HDL-C. Completers from six exercise studies were used in the present analysis: Whites (N = 473) and Blacks (N = 250) from the HERITAGE Family Study; Whites and Blacks from DREW (N = 326), from INFLAME (N = 70), and from STRRIDE (N = 303); and Whites from a University of Maryland cohort (N = 160) and from a University of Jyvaskyla study (N = 105), for a total of 1,687 men and women. Using the above definitions, 126 subjects (8.4%) had an adverse change in FI. Numbers of adverse responders reached 12.2% for SBP, 10.4% for TG, and 13.3% for HDL-C. About 7% of participants experienced adverse responses in two or more risk factors., Conclusions/significance: Adverse responses to regular exercise in cardiovascular and diabetes risk factors occur. Identifying the predictors of such unwarranted responses and how to prevent them will provide the foundation for personalized exercise prescription.

Introduction: It is generally accepted that if prediabetic individuals adopt healthy lifestyle habits, the progression to type 2 diabetes mellitus can be prevented or delayed. However, the role of exercise training independent of other lifestyle factors has not been determined. Furthermore, patients with type 2 diabetes mellitus have been shown to experience greater training-induced changes in glucose and insulin metabolism compared with healthy subjects, but the adaptations of prediabetic individuals have not been adequately examined. We hypothesized that (i) prediabetic subjects would have greater endurance training-induced changes in plasma glucose and insulin responses to an oral glucose challenge compared with age- and body mass index-matched normoglycemic subjects and (ii) training would completely reverse the abnormal glucose metabolism of prediabetic subjects., Methods: Plasma glucose and insulin responses to oral glucose tolerance tests (OGTTs) were examined in normoglycemic (n = 119) and prediabetic (n = 47) older men and women before and after a 6-month standardized endurance exercise training program., Results: Prediabetic subjects had greater glucose and insulin OGTT responses than normoglycemic subjects both before and after training (P < 0.05). Prediabetic subjects had greater training-induced changes in glucose and insulin areas under the glucose tolerance curve, as well as greater changes in glucose and insulin concentrations at several points of the OGTT. However, these changes did not eliminate the baseline differences in glucose tolerance between normoglycemic and prediabetic subjects. The between-group differences in changes in glucose and insulin variables were largely independent of changes in body weight or composition., Conclusions: Our data indicate that prediabetes is associated with greater training-induced changes in glucose tolerance. However, 6 months of endurance training alone was not sufficient to completely reverse prediabetes.

Our objective was to test the hypothesis that a common polymorphism in the hepatic lipase (HL) gene (LIPC -514C>T, rs1800588) influences aerobic exercise training-induced changes in TG, very-low-density lipoprotein (VLDL), and high-density lipoprotein (HDL) through genotype-specific increases in lipoprotein lipase (LPL) activity and that sex may affect these responses. Seventy-six sedentary overweight to obese men and women aged 50-75 yr at risk for coronary heart disease (CHD) underwent a 24-wk prospective study of the LIPC -514 genotype-specific effects of exercise training on lipoproteins measured enzymatically and by nuclear magnetic resonance, postheparin LPL and HL activities, body composition by dual energy x-ray absorptiometry and computer tomography scan, and aerobic capacity. CT genotype subjects had higher baseline total cholesterol, HDL-C, HDL(2)-C, large HDL, HDL particle size, and large LDL than CC homozygotes. Exercise training elicited genotype-specific decreases in VLDL-TG (-22 vs. +7%; P < 0.05; CC vs. CT, respectively), total VLDL and medium VLDL, and increases in HDL-C (7 vs. 4%; P < 0.03) and HDL(3)-C with significant genotype×sex interactions for the changes in HDL-C and HDL(3)-C (P values = 0.01-0.02). There were also genotype-specific changes in LPL (+23 vs. -6%; P < 0.05) and HL (+7 vs. -24%; P < 0.01) activities, with LPL increasing only in CC subjects (P < 0.006) and HL decreasing only in CT subjects (P < 0.007). Reductions in TG, VLDL-TG, large VLDL, and medium VLDL and increases in HDL(3)-C and small HDL particles correlated significantly with changes in LPL, but not HL, activity only in CC subjects. This suggests that the LIPC -514C>T variant significantly affects training-induced anti-atherogenic changes in VLDL-TG, VLDL particles, and HDL through an association with increased LPL activity in CC subjects, which could guide therapeutic strategies to reduce CHD risk.

We hypothesized that prior exercise would prevent postprandial lipaemia (PPL)-induced increases in intracellular reactive oxygen species (ROS) in three distinct circulating angiogenic cell (CAC) subpopulations. CD34(+), CD31(+)/CD14(-)/CD34(-), and CD31(+)/CD14(+)/CD34(-) CACs were isolated from blood samples obtained from 10 healthy men before and 4 h after ingesting a high fat meal with or without ∼50 min of prior endurance exercise. Significant PPL-induced increases in ROS production in both sets of CD31(+) cells were abolished by prior exercise. Experimental ex vivo inhibition of NADPH oxidase activity and mitochondrial ROS production indicated that mitochondria were the primary source of PPL-induced oxidative stress. The attenuated increases in ROS with prior exercise were associated with increased antioxidant gene expression in CD31(+)/CD14(-)/CD34(-) cells and reduced intracellular lipid uptake in CD31(+)/CD14(+)/CD34(-) cells. These findings were associated with systemic cardiovascular benefits of exercise, as serum triglyceride, oxidized low density lipoprotein-cholesterol, and plasma endothelial microparticle concentrations were lower in the prior exercise trial than the control trial. In conclusion, prior exercise completely prevents PPL-induced increases in ROS in CD31(+)/CD14(-)/CD34(-) and CD31(+)/CD14(+)/CD34(-) cells. The mechanisms underlying the effects of exercise on CAC function appear to vary among specific CAC types.

We investigated the influence of acute and chronic endurance exercise on levels of intracellular nitric oxide (NO), superoxide (O₂·⁻), and expression of genes regulating the balance between these free radicals in CD34⁺ and CD34⁻ peripheral blood mononuclear cells (PBMCs; isolated by immunomagnetic cell separation). Blood samples were obtained from age- and body mass index (BMI)-matched endurance-trained (n = 10) and sedentary (n = 10) men before and after 30 min of exercise at 75% maximal oxygen uptake (·VO(₂max)). Baseline levels of intracellular NO (measured by DAF-FM diacetate) and O₂·⁻ (measured by dihydroethidium) were 26% (P < 0.05) and 10% (P < 0.05) higher, respectively, in CD34⁺ PBMCs from the sedentary group compared with the endurance-trained group. CD34⁺ PBMCs from the sedentary group at baseline had twofold greater inducible nitric oxide synthase (iNOS) mRNA and 50% lower endothelial NOS (eNOS) mRNA levels compared with the trained group (P < 0.05). The baseline group difference in O₂·⁻ was eliminated by acute exercise. Experiments with apocynin indicated that the training-related difference in O₂·⁻ levels was explained by increased NADPH oxidase activity in the sedentary state. mRNA levels of additional angiogenic and antioxidant genes were consistent with a more angiogenic profile in CD34⁺ cells of trained subjects. CD34⁻ PBMCs, examined for exploratory purposes, also displayed a more angiogenic mRNA profile in trained subjects, with vascular endothelial growth factor (VEGF) and eNOS being more highly expressed in trained subjects. Overall, our data suggest an association between the sedentary state and increased nitro-oxidative stress in CD34⁺ cells.

Cardiovascular disease (CVD) and CVD risk factors are highly heritable, and numerous lines of evidence indicate they have a strong genetic basis. While there is nothing known about the interactive effects of genetics and exercise training on CVD itself, there is at least some literature addressing their interactive effect on CVD risk factors. There is some evidence indicating that CVD risk factor responses to exercise training are also heritable and, thus, may have a genetic basis. While roughly 100 studies have reported significant effects of genetic variants on CVD risk factor responses to exercise training, no definitive conclusions can be generated at the present time, because of the lack of consistent and replicated results and the small sample sizes evident in most studies. There is some evidence supporting "possible" candidate genes that may affect these responses to exercise training: APO E and CETP for plasma lipoprotein-lipid profiles; eNOS, ACE, EDN1, and GNB3 for blood pressure; PPARG for type 2 diabetes phenotypes; and FTO and BAR genes for obesity-related phenotypes. However, while genotyping technologies and statistical methods are advancing rapidly, the primary limitation in this field is the need to generate what in terms of exercise intervention studies would be almost incomprehensible sample sizes. Most recent diabetes, obesity, and blood pressure genetic studies have utilized populations of 10,000-250,000 subjects, which result in the necessary statistical power to detect the magnitude of effects that would probably be expected for the impact of an individual gene on CVD risk factor responses to exercise training. Thus at this time it is difficult to see how this field will advance in the future to the point where robust, consistent, and replicated data are available to address these issues. However, the results of recent large-scale genomewide association studies for baseline CVD risk factors may drive future hypothesis-driven exercise training intervention studies in smaller populations addressing the impact of specific genetic variants on well-defined physiological phenotypes.

This review of the exercise genomics literature emphasizes the strongest articles published in 2010 as defined by sample size, quality of phenotype measurements, quality of the exercise program or physical activity exposure, study design, adjustment for multiple testing, quality of genotyping, and other related study characteristics. One study on voluntary running wheel behavior was performed in 448 mice from 41 inbred strains. Several quantitative trait loci for running distance, speed, and duration were identified. Several studies on the alpha-3 actinin (ACTN3) R577X nonsense polymorphism and the angiotensin-converting enzyme (ACE) I/D polymorphism were reported with no clear evidence for a joint effect, but the studies were generally underpowered. Skeletal muscle RNA abundance at baseline for 29 transcripts and 11 single nucleotide polymorphisms (SNPs) were both found to be predictive of the V˙O2max response to exercise training in one report from multiple laboratories. None of the 50 loci associated with adiposity traits are known to influence physical activity behavior. However, physical activity seems to reduce the obesity-promoting effects of at least 12 of these loci. Evidence continues to be strong for a role of gene-exercise interaction effects on the improvement in insulin sensitivity after exposure to regular exercise. SNPs in the cAMP-responsive element binding position 1 (CREB1) gene were associated with training-induced HR response, in the C-reactive protein (CRP) gene with training-induced changes in left ventricular mass, and in the methylenetetrahydrofolate reductase (MTHFR) gene with carotid stiffness in low-fit individuals. We conclude that progress is being made but that high-quality research designs and replication studies with large sample sizes are urgently needed., (© 2011 by the American College of Sports Medicine)

The discovery of circulating angiogenic cells (CAC) with cardiovascular regenerative potential has transformed our understanding of the health and maintenance of cardiovascular tissues. We will describe the influence of acute exercise and exercise training on CAC characteristics and evidence for mechanisms that may be important in the optimization of CAC potential.

As part of the insulin signalling pathway, Akt influences growth and metabolism. The AKT1 gene G205T (rs1130214) polymorphism has potential functional effects. Thus, we determined whether the G205T polymorphism influences metabolic variables and their responses to aerobic exercise training. Following dietary stabilization, healthy, sedentary, 50- to 75-year-old Caucasian men (n = 51) and women (n = 58) underwent 6 months of aerobic exercise training. Before and after completing the intervention, dual-energy X-ray absorptiometry was used to measure percentage body fat, computed tomography to measure visceral and subcutaneous fat, and oral glucose tolerance testing to measure glucose total area under the curve (AUC), insulin AUC and insulin sensitivity. Taqman assay was used to determine AKT1 G205T genotypes. At baseline, men with the GG genotype (n = 29) had lower maximal oxygen consumption (VO2 max) values (P = 0.026) and higher percentage body fat (P = 0.046), subcutaneous fat (P = 0.021) and insulin AUC (P = 0.003) values than T allele carriers (n = 22). Despite their rather disadvantageous starting values, men with the GG genotype seemed to respond to exercise training more robustly than men with the T allele, highlighted by significantly greater fold change improvements in insulin AUC (P = 0.012) and glucose AUC (P = 0.035). Although the GG group also significantly improved VO2 max with training, the change in VO2 max was not as great as that of the T allele carriers (P = 0.037). In contrast, after accounting for hormone replacement therapy use, none of the variables differed in the women at baseline. As a result of exercise training, women with the T allele (n = 20) had greater fold change improvements in fasting glucose (P = 0.011), glucose AUC (P = 0.017) and insulin sensitivity (P = 0.044) than GG genotype women (n = 38). Our results suggest that the AKT1 G205T polymorphism influences metabolic variables and their responses to aerobic exercise training in older, previously sedentary individuals.

Acute exercise and exercise training may influence putative endothelial progenitor cell (EPC) number and colony forming units (CFU-ECs), although the mechanisms remain unclear. This study examined the effects of in vitro thrombin supplementation and acute exercise on CFU-EC gene expression, associated with cellular proliferation and differentiation. The effect of habitual physical activity was evaluated through analysis of EPCs from chronically high- and low-active men. Participants were healthy high- and low-active men (n=23), aged 55-80 yr. Circulating CD34+/VEGFR2+ number, CFU-ECs, plasma prothrombin fragment (F1+2), and thrombin-antithrombin III were measured at rest and after 30 min of exercise. Gene expression of cyclin A2, cyclin D1, p27, VE-cadherin, and VEGFR2 was assessed in postexercise CFU-ECs and resting CFU-ECs treated with 0, 1, 5, or 10 U/ml of thrombin. Outcomes were compared between high- and low-active participants. F1+2 and thrombin-antithrombin III, but not CD34+/VEGFR2+ number and CFU-ECs, increased with exercise. Exercise-induced changes in F1+2 correlated with changes in CD34+/VEGFR2+ number in both groups. Thrombin treatments and acute exercise increased cyclin A2 and cyclin D1 expression and decreased p27 expression. One unit per milliliter thrombin increased VEGFR2 and VE-cadherin expression, whereas 5 U/ml, 10 U/ml, and acute exercise did not elicit any changes. An exercise training effect was observed with greater decreases in p27 expression with 5 and 10 U/ml thrombin and greater increases in VEGFR2 and VE-cadherin expression with 1 U/ml thrombin in high-active men. Exercise-induced changes in putative EPC gene expression are associated with thrombin production and may be modulated by long-term exercise training.

An annual review publication of the most significant articles in exercise, fitness, and performance genomics begins with this article, which covers 2 yr, 2008 and 2009. The review emphasizes the strongest articles as defined by sample size, quality of phenotype measurements, quality of the exercise program or physical activity exposure, study design, adjustment for multiple testing, quality of genotyping, and other related study characteristics. With this avowed focus on the highest quality articles, only a small number of published articles are reviewed. Among the most significant findings reported here are a brief overview of the first genome-wide association study of the genetic differences between exercisers and nonexercisers. In addition, the latest results on the actinin alpha 3 (ACTN3) R577X nonsense polymorphism are reviewed, emphasizing that no definitive conclusion can be reached at this time. Recent studies that have dealt with mitochondrial DNA haplogroups and endurance performance are described. Published reports indicating that physical activity may attenuate the effect of the fat mass and obesity associated (FTO) gene risk allele on body mass index are reviewed. Articles that have tested the contributions of specific genes to the response of glucose and insulin metabolism traits to regular exercise or physical activity level are considered and found to be generally inconclusive at this stage. Studies examining ethnic differences in the response of blood lipids and lipoproteins to exercise training cannot unequivocally relate these to apolipoprotein E (APOE) genotypes. Hemodynamic changes with exercise training were reported to be associated to sequence variation in kinesin heavy chain (KIF5B), but no replication study is available as of yet. We conclude from this first installment that exercise scientists need to prioritize high-quality research designs and that replication studies with large sample sizes are urgently needed.

Perilipins are lipid droplet-coating proteins that regulate intracellular lipolysis in adipocytes. A haplotype of two perilipin gene (PLIN) single nucleotide polymorphisms, 13041A>G and 14995A>T, has been previously associated with obesity risk. Furthermore, the available data indicate that this association may be modified by sex. We hypothesized that this haplotype would associate with body fatness, aerobic fitness, and a number of cardiovascular (CV) risk factor phenotypes before and after a 6-mo endurance exercise training program in sedentary older Caucasians. The major haplotype group (13041A/14995A; n = 57) had significantly lower body mass index (BMI) and body fatness compared with noncarriers of the AA haplotype (n = 44) before the training intervention. Training improved body composition in both groups, but fatness remained higher in noncarriers than AA carriers after training. This fat retention in noncarriers blunted their maximal oxygen uptake (Vo(2 max)) adaptation to training. Female noncarriers had substantially higher concentrations of several conventionally and NMR-measured HDL-C subfractions than male noncarriers before and after training, but only minimal differences were found between the sexes in the AA haplotype group. Haplotype group differences in baseline and after-training responses to an oral glucose tolerance test (OGTT) also differed by sex, as noncarrier men had the highest baseline area under the insulin curve (insulin AUC), but were the only group to significantly improve insulin AUC with training. The insulin sensitivity index and plasma glucose responses to the OGTT were more favorable in AA carriers than noncarriers before and after training. Overall, our findings suggest that PLIN variation explains some of the interindividual differences in the response of obesity and CV phenotypes to exercise training. Furthermore, these data contribute to the growing understanding of PLIN as a candidate gene for human obesity and the cardiometabolic consequences of excess adiposity.

We sought to delineate the effects of acute and chronic exercise on the regulation of intracellular nitric oxide (NO(i)) production in putative endothelial progenitor cells (EPCs). Putative EPC colony-forming units (CFU-EC) were cultured from blood drawn before and after 30 min of treadmill exercise at 75% of maximal oxygen uptake in active (n = 8) and inactive (n = 8) men. CFU-EC were similar between groups at baseline, but increased after exercise in active men only (P = 0.04). CFU-EC expressed lower NADPH oxidase subunit gp91(phox) mRNA and elevated endothelial nitric oxide synthase mRNA in active relative to inactive men at baseline (P < 0.05). Acute exercise reduced gp91(phox) mRNA in CFU-EC of both groups (P < 0.05), whereas p47(phox) mRNA levels were reduced in the inactive group only (P = 0.02). There were no differences between groups or with acute exercise in xanthine oxidase, superoxide dismutase isoforms, or gluthathione peroxidase-1 mRNA levels. NO(i) was significantly greater in CFU-EC of active men at baseline (P = 0.004). NO(i) increased in CFU-EC of inactive men with acute exercise, and in vitro experiments with apocynin indicated the increased NO(i) production was caused by suppression of NADPH oxidase. However, the increases in NO(i) with the different treatments in the inactive group did not reach the baseline levels in the active group (P < 0.05). We conclude that acute exercise increases NO(i) in cells generated by the CFU-EC assay through an NADPH oxidase-inhibition mechanism in sedentary men. However, differences due to chronic exercise must involve additional factors. Our findings support exercise as a means to improve putative EPC function and suggest a novel mechanism that may explain this effect.

Introduction: Oxidative stress that is mediated through NADPH oxidase activity plays a role in the pathology of hypertension, and aerobic exercise training reduces NADPH oxidase activity. The involvement of genetic variation in the p22phox (CYBA) subunit genes in individual oxidative stress responses to aerobic exercise training has yet to be examined in Pre and Stage 1 hypertensives., Methods: Ninety-four sedentary Pre and Stage 1 hypertensive adults underwent 6 months of aerobic exercise training at a level of 70% VO2max to determine whether the CYBA polymorphisms, C242T and A640G, were associated with changes in urinary 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), urinary nitric oxide metabolites (NOx), and plasma total antioxidant capacity (TAC)., Results: Demographic and subject characteristics were similar among genotype groups for both polymorphisms. At baseline, a significant (P = 0.03) difference among the C2424T genotype groups in 8-iso-PGF2alpha levels was detected, with the TT homozygotes having the lowest levels and the CC homozygotes having the highest levels. However, no differences were found at baseline between the A640G genotype groups. After 6 months of aerobic exercise training, there was a significant increase in VO2max (P < 0.0001) in the entire study population. In addition, there were significant increases in both urinary 8-iso-PGF2alpha (P = 0.002) and plasma TAC (P=0.03) levels and a significant decrease in endogenous urinary NOx (P < 0.0001). Overall, aerobic exercise training elicited no significant differences among genotype groups in either CYBA variant for any of the oxidative stress variables., Conclusions: We found that compared with CYBA polymorphisms C242T and A640G, it was aerobic exercise training that had the greatest influence on the selected biomarkers; furthermore, our results suggest that the C242T CYBA variant influences baseline levels of urinary 8-iso-PGF2alpha but not the aerobic exercise-induced responses.

The lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) expressed on vascular cells plays a major role in atherogenesis by internalizing and degrading oxidized low-density lipoprotein. LOX-1 can be cleaved from the cell surface and released as soluble LOX-1 (sLOX-1), and elevated sLOX-1 levels may be indicative of atherosclerotic plaque instability. We examined associations between the LOX-1 gene 3'UTR-C/T and G501C polymorphisms and plasma sLOX-1 levels in 97 healthy older men and women. The frequencies for the 3'UTR-T and 501C alleles were 46 and 10%, respectively. Plasma sLOX-1 levels were significantly higher in the 3'UTR CC genotype group compared with both the CT (P=0.02) and TT genotype groups (P=0.002). Plasma sLOX-1 levels were also significantly higher in the 501GC genotype group compared with the GG genotype group (P=0.004). In univariate analyses, sLOX-1 levels were significantly associated with both the 3'UTR-C/T and G501C polymorphisms. These associations remained significant after adjusting for age, sex, race and body mass index. In conclusion, variation in the LOX-1 gene is associated with plasma sLOX-1 levels in older men and women.

We investigated the association between soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) levels and obesity in older women. Fifty-one postmenopausal women (10 lean, 22 overweight, and 19 obese) were included in this small retrospective analysis. Plasma sLOX-1 levels were measured using a chemiluminescent enzyme-linked immunoassay. Plasma levels of sLOX-1 were significantly higher in obese women (55.33 +/- 4.49 pg/ml) compared to lean (30.91 +/- 6.19 pg/ml, P = 0.002) and overweight women (38.31 +/- 4.18 pg/ml, P = 0.017). Plasma sLOX-1 levels were positively associated with body weight, BMI, total body fat, and trunk fat. The relationship between sLOX-1 and BMI was attenuated after adjustment for age, hormone replacement therapy, and body fat. In conclusion, obese women have higher sLOX-1 levels, which may reflect increased LOX-1 expression in adipose tissue.

Our objective was to investigate the relationship between the E23K genetic variant in the KCNJ11 gene, which encodes for the Kir6.2 subunit of the inward rectifier K+ channel family, and glucose and insulin metabolism and cardiovascular (CV) function in the sedentary state and their responses to exercise training. Two hundred and fourteen healthy sedentary men and women aged 50-75 years old and free of CV disease and type 2 diabetes underwent baseline testing (maximal oxygen consumption (Vo2max), body composition and glucose tolerance). One hundred and sixty-three of them repeated these tests after 24 weeks of exercise training while on a low-fat diet. At baseline, age, height, body fat, resting systolic blood pressure and all glucose and insulin metabolism markers did not differ among E23K genotype groups. In women at baseline, E23K genotype was associated with body weight, body mass index, Vo2max (ml kg(-1) min(-1), l min(-1)) and maximal minute ventilation. In men at baseline, E23K genotype was significantly associated with maximal heart rate, maximal respiratory exchange ratio and diastolic blood pressure at rest. Numerous glucose and insulin metabolism and CV function phenotypes changed significantly with exercise training in the total population. The E23K genotype did not significantly influence any of these training-induced changes. Thus, the common E23K genetic variant at the KCNJ11 gene locus was significantly associated with CV function in the untrained state, although the associations appear to differ between men and women. However, this variant has no significant effect on training-induced CV and glucose and insulin metabolism adaptations.

To examine the influence of insulin-like growth factor (IGF) pathway gene polymorphisms on muscle mass and strength responses to strength training (ST), we studied 128 White and Black men and women before and after a 10-wk single-leg knee extension ST program. One-repetition maximum strength, muscle volume (MV) via computed tomography, and muscle quality (MQ) were assessed at baseline and after 10 wk of ST. There was a significant combined IGF1 cytosine adenine (CA) repeat gene effect, which included both the IGF1 CA repeat main effect and IGF1 CA repeat x PPP3R1 insertion-deletion (I/D) gene x gene interaction effect, on the changes in strength (P < 0.01) and MQ (P < 0.05) with ST. There was a trend for a significant gene x gene interaction between IGF1 CA repeat and PPP3R1 I/D for changes in strength (P = 0.07) and MQ (P = 0.06) with ST. The influence of the PPP3R1 A-202C gene polymorphism on change in MV with ST approached significance (P = 0.06). The IGF1 CA repeat polymorphism had a significant influence on the change in strength and MV combined with ST (P < 0.05), whereas the influence of the PPP3R1 I/D polymorphism approached significance (P = 0.08). There were no associations between the IGFBP3 A-202C gene polymorphism and the muscle phenotypic responses to ST. These data suggest that two of the three IGF pathway gene polymorphisms identified in this study influence muscle phenotypic responses to ST in both black and white older men and women.

In endothelial cells, NF-kappaB is an important intracellular signaling molecule by which changes in wall shear stress are transduced into the nucleus to initiate downstream endothelial nitric oxide synthase (NOS3) gene expression. We investigated whether NF-kappa light-chain gene enhancer in B cells 1 (NFKB1) promoter polymorphism ((-94)NFKB1 I/D, where I is the insertion allele and D is the deletion allele) was associated with 1) NOS3 gene expression in endothelial cells under physiological levels of unidirectional laminar shear stress (LSS) and 2) endothelial function in prehypertensive and stage I hypertensive individuals before and after a 6-mo supervised endurance exercise intervention. Competitive EMSAs revealed that proteins present in the nuclei of endothelial cells preferentially bound to the I allele NFKB1 promoter compared with the D allele. Reporter gene assays showed that the I allele promoter had significantly higher activity than the D allele. In agreement with these observations, homozygous II genotype cells had higher p50 expression levels than homozygous DD genotype cells. Cells with the homozygous II genotype showed a greater increase in NOS3 protein expression than did homozygous DD genotype cells under LSS. Functional experiments on volunteers confirmed higher baseline reactive hyperemic forearm blood flow, and, furthermore, the subgroup analysis revealed that DD homozygotes were significantly less prevalent in the exercise responder group compared with II and ID genotypes. We conclude that the (-94)NFKB1 I/D promoter variation contributes to the modulation of vascular function and adaptability to exercise-induced flow shear stress, most likely due to differences in NFKB1 gene transactivity.

Unlabelled: The coagulation cascade plays a critical role in the development of cardiovascular disease (CVD). Elevated plasma prothrombin fragment 1 + 2 (F1 + 2) and factor VIII antigen (FVIII:Ag) levels have been associated with a hypercoagulable state, enhancing the risk for vascular thrombotic events. Aerobic training is known to reduce CVD risk, and an improved coagulation profile may contribute to this reduction., Purpose: To analyze the effect of 6 months of standardized aerobic exercise training on resting F1 + 2 and FVIII:Ag levels in men and postmenopausal women aged 50-75 while accounting for several possibly confounding factors., Materials and Methods: Sedentary men (N=16) and women (N=31) underwent supervised aerobic training 3 d x wk(-1) for 6 months while maintaining the American Heart Association step 1 diet. Baseline and final testing included measurement of F1 + 2, FVIII:Ag, plasma lipoprotein-lipid levels, body composition, and VO2max., Results: When adjusted for baseline values and changes in diastolic blood pressure with training, F1 + 2 was found to decrease significantly with exercise training from 1.493 +/- 0.058 to 1.422 +/- 0.059 nM (P=0.014). FVIII:Ag levels were found to increase significantly with training when adjusted for baseline values, from 152.5 +/- 6.7% of standard at baseline to 156.0 +/- 6.1% of standard at final testing (P=0.005). Training-induced changes in coagulation markers were independent of changes in blood lipids, aerobic capacity, and body composition., Conclusions: : These results indicate that endurance training has a significant impact on the coagulation cascade, reducing coagulation activity in the common pathway and thrombin formation at rest while increasing the activation potential of the intrinsic pathway.

Background: A common functional missense mutation [Ala54Thr of the fatty acid-binding protein 2 gene (FABP2)] has previously been studied for associations with glucoregulation, postprandial lipemia, and lipid oxidation rates. However, most of those studies have not accounted for the interactive and potentially confounding effects of habitual physical activity and diet., Objective: We tested the hypothesis that, in sedentary nondiabetic subjects following a low-fat diet, Thr54 FABP2 carriers have lower glucoregulatory function, greater postprandial lipemia, and greater lipid oxidation rates than do their Ala54 FABP2-homozygous counterparts., Design: Men and women (n = 122) aged 50-75 y who were following a low-fat diet were genotyped and underwent oral-glucose-tolerance tests. A subgroup (n = 36) also underwent postprandial lipemia tests with lipid oxidation rate measurements., Results: Thr54 carriers were less likely to have normal glucose tolerance (P = 0.05) and had higher fasting glucose concentrations (P = 0.003) than did Ala54 homozygotes. In Thr54 carriers, the insulin sensitivity index was lower (P = 0.02), and the fasting insulin and the oral-glucose-tolerance test insulin area under the curve were higher (P = 0.05 and 0.03, respectively) than in Ala54 homozygotes. FABP2 genotype was not associated with fasting or postprandial lipemia test triacylglycerol or free fatty acids (P > or = 0.22 for all), but postprandial lipid oxidation rates were higher (P = 0.01), which suggests that fat absorption is higher in Thr54 carriers than in Ala54 homozygotes., Conclusions: In sedentary nondiabetic persons following a low-fat diet, FABP2 Thr54 carriers have lower glucose tolerance and lower insulin action than do Ala54-homozygous persons. Furthermore, FABP Thr54 carriers have higher lipid oxidation rates, which may be the mechanism of glucoregulatory dysfunction.

The current review presents the 2005 update of the human gene map for physical performance and health-related fitness phenotypes. It is based on peer-reviewed papers published by the end of 2005. The genes and markers with evidence of association or linkage with a performance or fitness phenotype in sedentary or active people, in adaptation to acute exercise, or for training-induced changes are positioned on the genetic map of all autosomes and the X chromosome. Negative studies are reviewed, but a gene or locus must be supported by at least one positive study before being inserted on the map. By the end of 2000, in the early version of the gene map, 29 loci were depicted. In contrast, the 2005 human gene map for physical performance and health-related phenotypes includes 165 autosomal gene entries and QTL, plus five others on the X chromosome. Moreover, there are 17 mitochondrial genes in which sequence variants have been shown to influence relevant fitness and performance phenotypes. Thus, the map is growing in complexity. Unfortunately, progress is slow in the field of genetics of fitness and performance, primarily because the number of laboratories and scientists focused on the role of genes and sequence variations in exercise-related traits continues to be quite limited.

Chronic hypertriglyceridemia is thought to be atherogenic and is associated with an elevated thrombotic potential, both of which may be improved with aerobic exercise training. Eight subjects were tested for aerobic capacity, body composition, and postprandial lipemia (PPL), followed by 6 mo of exercise training and final testing. Blood samples were obtained for measurement of free fatty acid (FFA), triglycerides (TG), insulin (Ins), and glucose (Glu). Hemostatic variables including factor VII activity (FVIIa), tissue factor pathway inhibitor-factor Xa complex (TFPI/Xa), and plasminogen activator inhibitor-1 (PAI-1) antigen/activity as well as leukocyte tumor necrosis factor-alpha (TNF-alpha) gene expression were determined among four subjects. We found that the exercise training was of sufficient intensity to increase aerobic capacity (P < 0.0001) and improve body composition (P = 0.04). There were no differences between tests among PPL responses of FFA, TG, Ins, or Glu; however, the mean TG response and fat oxidation rate improved. PAI-1 antigen/activity, FVIIa, TFPI/Xa, and TNF-alpha gene expression were all improved after exercise training after adjusting for confounders. We conclude that aerobic exercise training reduces the potential for coagulation, improves fibrinolytic potential, and reduces leukocyte TNF-alpha gene expression after the ingestion of a high-fat meal.