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Background: An elevated lipoprotein insulin resistance (LP-IR) score corresponds to insulin resistance in adults with overweight and obesity, yet data are lacking regarding the impact of exercise interventions on LP-IR. The purpose of this secondary analysis was to evaluate the effects of a weight loss and weight maintenance intervention on LP-IR score in adults with overweight and obesity. Methods: Thirty sedentary adults with overweight and obesity completed a 10-week OPTIFAST® weight loss program with supervised aerobic exercise to achieve clinical weight loss (CWL) (≥7% from baseline). Aerobic exercise volume increased weekly until 700 MET min/week was reached. Participants who reached CWL were randomized to groups at volumes at either physical activity (PA-REC) or weight maintenance (WM-REC) recommendations (weeks 11–28). Plasma blood samples were analyzed via nuclear magnetic resonance spectroscopy at baseline, after weight loss (week 10), and following weight maintenance (week 28). Results: Following the weight loss phase, on average, participants significantly (p < 0.001) reduced LP-IR score (−12.1 ± 13.5), body weight (−8.9 ± 2.7%), and waist circumference (−7.7 ± 4.1 cm). During the weight maintenance phase, there were no changes in LP-IR score between exercise groups (PA-REC: 4.1 ± 13.6; WM-REC: −2.0 ± 11.2; P = 0.7). The PA-REC group had improvements in LP-IR score from baseline (49.8 ± 24.6 to 36.6 ± 27.6, P < 0.001), yet there were no within-group changes during the weight maintenance phase (P > 0.05). Conclusion: LP-IR score improved during weight loss in adults with overweight and obesity and were sustained during the weight maintenance phase in the PA-REC group. Aerobic exercise at least at minimum guidelines following CWL can preserve LP-IR score improvements and may indicate a reduced T2DM risk in adults with overweight and obesity. [ABSTRACT FROM AUTHOR]

Background: Standardized exercise protocols have been shown to improve overall cardiovascular fitness, but direct effects on left ventricular (LV) function, particularly diastolic function and relation to post-transcriptional molecular pathways (microRNAs (miRs)) are poorly understood. This project tested the central hypothesis that adaptive LV remodeling resulting from a large animal exercise training protocol, would be directly associated with specific miRs responsible for regulating pathways relevant to LV myocardial stiffness and geometry. Methods and results: Pigs (n = 9; 25 Kg) underwent a 4 week exercise training protocol (10 degrees elevation, 2.5 mph, 10 min, 5 days/week) whereby LV chamber stiffness (KC) and regional myocardial stiffness (rKm) were measured by Doppler/speckle tracking echocardiography. Age and weight matched non-exercise pigs (n = 6) served as controls. LV KC fell by approximately 50% and rKm by 30% following exercise (both p < 0.05). Using an 84 miR array, 34 (40%) miRs changed with exercise, whereby 8 of the changed miRs (miR-19a, miR-22, miR-30e, miR-99a, miR-142, miR-144, miR-199a, and miR-497) were correlated to the change in KC (r ≥ 0.5 p < 0.05) and mapped to matrix and calcium handling processes. Additionally, miR-22 and miR-30e decreased with exercise and mapped to a localized inflammatory process, the inflammasome (NLRP-3, whereby a 2-fold decrease in NLRP-3 mRNA occurred with exercise (p < 0.05). Conclusion: Chronic exercise reduced LV chamber and myocardial stiffness and was correlated to miRs that map to myocardial relaxation processes as well as local inflammatory pathways. These unique findings set the stage for utilization of myocardial miR profiling to identify underlying mechanisms by which exercise causes changes in LV myocardial structure and function. [ABSTRACT FROM AUTHOR]

Submaximal exercise capacity is an indicator of cardiorespiratory fitness with clinical and public health implications. Submaximal exercise capacity and its response to exercise programs are characterized by heritability levels of about 40%. Using physical working capacity (power output) at a heart rate of 150 beats/min (PWC150) as an indicator of submaximal exercise capacity in subjects of the HERITAGE Family Study, we have undertaken multi-omics and in silico explorations of the underlying biology of PWC150 and its response to 20 wk of endurance training. Our goal was to illuminate the biological processes and identify panels of genes associated with human variability in intrinsic PWC150 (iPWC150) and its trainability (dPWC150). Our bioinformatics approach was based on a combination of genome-wide association, skeletal muscle gene expression, and plasma proteomics and metabolomics experiments. Genes, proteins, and metabolites showing significant associations with iPWC150 or dPWC150 were further queried for the enrichment of biological pathways. We compared genotype-phenotype associations of emerging candidate genes with reported functional consequences of gene knockouts in mouse models. We investigated the associations between DNA variants and multiple muscle and cardiovascular phenotypes measured in HERITAGE subjects. Two panels of prioritized genes of biological relevance to iPWC150 (13 genes) and dPWC150 (6 genes) were identified, supporting the hypothesis that genes and pathways associated with iPWC150 are different from those underlying dPWC150. Finally, the functions of these genes and pathways suggested that human variation in submaximal exercise capacity is mainly driven by skeletal muscle morphology and metabolism and red blood cell oxygen-carrying capacity. NEW & NOTEWORTHY Multi-omics and in silico explorations of the genes and underlying biology of submaximal exercise capacity and its response to 20 wk of endurance training were undertaken. Prioritized genes were identified: 13 genes for variation in submaximal exercise capacity in the sedentary state and 5 genes for the response level to endurance training, with no overlap between them. Genes and pathways associated with submaximal exercise capacity in the sedentary state are different from those underlying trainability. [ABSTRACT FROM AUTHOR]

This study aimed to assess if, during incremental exercise, considering individual characteristics can make the relationship between the percentages of heart rate (HRR) and oxygen uptake (V̇O2R) reserve either 1:1 or more accurate. Cycle ergometer data of the maximal incremental exercise tests performed by 450 healthy and sedentary participants (17-66 years) of the HERITAGE Family Study, grouped for sex, ethnicity, age, body fat, resting HR, and V̇O2max, were used to calculate the individual linear regressions between %HRR and %V̇O2R. The mean slope and intercept of the individual linear regressions of each subgroup were compared with 1 and 0 (identity line), respectively, using Hotelling tests followed by post-hoc one-sample t-tests. Two multiple linear regressions were also performed, using either the slopes or intercepts of the individual linear regressions as dependent variables and sex, age, resting HR, and V̇O2max as independent variables. The mean %HRR-%V̇O2R relationships of all subgroups differed from the identity line. Moreover, individual linear regression intercepts (8.9 ± 16.0) and slopes (0.971 ± 0.190) changed (p < 0.001) after 20 weeks of aerobic training (13.1 ± 11.1 and 0.891 ± 0.122). The multiple linear regressions could explain only 3.8% and 1.3% of the variance in the intercepts and slopes, whose variability remained high (standard error of estimate of 15.8 and 0.189). In conclusion, the %HRR-%V̇O2R relationship differs from the identity line regardless of individual characteristics and their difference increased after aerobic training. Moreover, due to the high interindividual variability, using a single equation for the whole population seems not suitable for representing the %HRR-%V̇O2R relationship of a given subject, even when several individual characteristics are considered. Highlights The association between %HRR and %V̇O2R is not 1:1 even when individuals are grouped by age, sex, ethnicity, body composition, HRrest, and V̇O2max. Using several subject characteristics to identify the individual's %HRR-%V̇O2R relationship does not meaningfully increase its prediction accuracy or reduce the interindividual variability of %HRR-%V̇O2R relationships Using a single equation for the whole population is not suitable for representing the relationship of a given subject; hence, individual relationships should be preferred when prescribing the intensity of aerobic exercise. The individual %HRR-%V̇O2R relationship should be periodically assessed due to the potential training induced changes in the relationship. [ABSTRACT FROM AUTHOR]

Background: This study examined the cross-sectional and longitudinal associations of cardiorespiratory fitness (CRF) and ideal cardiovascular health (CVH). Methods: CRF and the 7 CVH components were measured in 11,590 (8865 males; 2725 females) adults at baseline and in 2532 (2160 males; 372 females) adults with at least one follow-up examination from the Aerobics Center Longitudinal Study. Ideal CVH score was calculated as a composite of 7 measures, each scored 0 to 2. CVH groups were based on participant point score: ≤7 (poor), 8 to 11 (intermediate), and 12 to 14 (ideal). Analyses included general linear, logistic regression, and linear mixed models. Results: At baseline, participants in the high CRF category had 21% and 45% higher mean CVH scores than those in the moderate and poor CRF categories (P < .001). The adjusted odds (95% confidence interval) of being in the poor CVH group at baseline were 4.9 (4.4-5.4) and 16.9 (14.3-19.9) times greater for individuals with moderate and low CRF, respectively, compared with those with high CRF (P < .001). Longitudinal analysis found that for every 1-minute increase in treadmill time, CVH score increased by 0.23 units (P < .001) independent of age, sex, exam number, and exam year. Conclusions: Higher CRF is associated with better CVH profiles, and improving CRF over time is independently associated with greater improvements in CVH. [ABSTRACT FROM AUTHOR]

Aims Apolipoprotein C-II (ApoC-II) is thought to activate lipoprotein lipase (LPL) and is therefore a possible target for treating hypertriglyceridemia. Its relationship with cardiovascular risk has not been investigated in large-scale epidemiologic studies, particularly allowing for apolipoprotein C-III (ApoC-III), an LPL antagonist. Furthermore, the exact mechanism of ApoC-II–mediated LPL activation is unclear. Methods and results ApoC-II was measured in 3141 LURIC participants of which 590 died from cardiovascular diseases during a median (inter-quartile range) follow-up of 9.9 (8.7–10.7) years. Apolipoprotein C-II–mediated activation of the glycosylphosphatidylinositol high-density lipoprotein binding protein 1 (GPIHBP1)–LPL complex was studied using enzymatic activity assays with fluorometric lipase and very low-density lipoprotein (VLDL) substrates. The mean ApoC-II concentration was 4.5 (2.4) mg/dL. The relationship of ApoC-II quintiles with cardiovascular mortality exhibited a trend toward an inverse J-shape, with the highest risk in the first (lowest) quintile and lowest risk in the middle quintile. Compared with the first quintile, all other quintiles were associated with decreased cardiovascular mortality after multivariate adjustments including ApoC-III as a covariate (all P < 0.05). In experiments using fluorometric substrate-based lipase assays, there was a bell-shaped relationship for the effect of ApoC-II on GPIHBP1–LPL activity when exogenous ApoC-II was added. In ApoC-II-containing VLDL substrate-based lipase assays, GPIHBP1–LPL enzymatic activity was almost completely blocked by a neutralizing anti-ApoC-II antibody. Conclusion The present epidemiologic data suggest that increasing low circulating ApoC-II levels may reduce cardiovascular risk. This conclusion is supported by the observation that optimal ApoC-II concentrations are required for maximal GPIHBP1–LPL enzymatic activity. [ABSTRACT FROM AUTHOR]

High-throughput proteomics allows researchers to simultaneously explore the roles of thousands of biomarkers in the pathophysiology of diabetes. We conducted proteomic association studies of incident type 2 diabetes and physiologic responses to an intravenous glucose tolerance test (IVGTT) to identify novel protein contributors to glucose homeostasis and diabetes risk. We tested 4,776 SomaScan proteins measured in relation to 18-year incident diabetes risk in participants from the Cardiovascular Health Study (N = 2,631) and IVGTT-derived measures in participants from the HERITAGE Family Study (N = 752). We characterize 51 proteins that were associated with longitudinal diabetes risk, using their respective 39, 9, and 8 concurrent associations with insulin sensitivity index (SI), acute insulin response to glucose (AIRG), and glucose effectiveness (SG). Twelve of the 51 diabetes associations appear to be novel, including β-glucuronidase, which was associated with increased diabetes risk and lower SG, suggesting an alternative pathway to insulin for glucose disposal; and plexin-B2, which also was associated with increased diabetes risk, but with lower AIRG, and not with SI, indicating a mechanism related instead to pancreatic dysfunction. Other novel protein associations included alcohol dehydrogenase-1C, fructose-bisphosphate aldolase-B, sorbitol dehydrogenase with elevated type 2 diabetes risk, and a leucine-rich repeat containing protein-15 and myocilin with decreased risk. Article Highlights: Plasma proteins are associated with the risk of incident diabetes in older adults independent of various demographic, lifestyle, and biochemical risk factors. These same proteins are associated with subtle differences in measures of glucose homeostasis earlier in life. Proteins that are associated with lower insulin sensitivity in individuals without diabetes tend to be associated with appropriate compensatory mechanisms, such as a stronger acute insulin response or higher glucose effectiveness. Proteins that are associated with future diabetes risk, but not with insulin insensitivity, tend to be associated with lower glucose effectiveness and/or impaired acute insulin response. [ABSTRACT FROM AUTHOR]

Excessive gestational weight gain (GWG) is associated with adverse pregnancy outcomes. This metabolome-wide association study aimed to identify metabolomic markers for GWG. This longitudinal study included 39 Black and White pregnant women with a prepregnancy body mass index (BMI) of ≥ 25 kg/m2. Untargeted metabolomic profiling was performed using fasting plasma samples collected at baseline (mean: 12.1 weeks) and 32 weeks of gestation. The associations of metabolites at each time point and changes between the two time points with GWG were examined by linear and least absolute shrinkage and selection operator (LASSO) regression analyses. Pearson correlations between the identified metabolites and cardiometabolic biomarkers were examined. Of the 769 annotated metabolites, 88 metabolites at 32 weeks were individually associated with GWG, with four (phosphatidylcholine (PC) 34:4, triacylglycerol (TAG) 52:6, arachidonic acid, isoleucine) jointly associated with GWG (area under the receiver operating characteristic curve (AUC) for excessive GWG: 0.80, 95% CI: 0.67, 0.93). No correlations were observed between the 88 metabolites and insulin, C-peptide, and high-sensitivity C-reactive protein at 32 weeks. Twelve metabolites at baseline (AUC for excessive GWG: 0.80, 95% CI: 0.62, 0.99) and three metabolite changes (AUC for excessive GWG: 0.73, 95% CI: 0.44, 1.00) were jointly associated with GWG. We identified novel metabolites in the first and third trimesters associated with GWG, which may shed light on the pathophysiology of GWG. [ABSTRACT FROM AUTHOR]

Background: Whether higher cardiorespiratory fitness (CRF) confers protection against cardiovascular disease (CVD) in individuals with manifest hypercholesterolemia is poorly understood. Methods: Participants were 8920 men aged 20–82 years with hypercholesterolemia but no history of CVD and/or cancer and who received a preventive examination at the Cooper Clinic in Dallas, TX, USA, during 1974–2001. CRF was quantified as maximal treadmill test duration and was grouped for analysis as low, moderate, or high based on the traditional Aerobics Center Longitudinal Study cutpoints. Using Cox regression analyses, we computed hazard ratios and 95% confidence intervals for risk of mortality based on CRF. Results: During an average of 17 years of follow-up, 329 CVD and 290 cancer deaths occurred. After control for baseline age, examination year, body mass index, total cholesterol, smoking, alcohol intake, physical activity, hypertension, diabetes, and parental history of CVD, hazard ratios (95% confidence interval) for CVD deaths across moderate and high categories of CRF (with low fit as referent) were: 0.66 (0.50–0.87) and 0.55 (0.39–0.79), respectively. There was an inverse association between CRF and CVD death among normal-weight (trend p < 0.0001), younger (<60 y, trend p = 0.01), and inactive men (trend p = 0.002). However, no significant association was found between CRF and cancer mortality. Conclusions: Among men with hypercholesterolemia, higher CRF was associated with a lower risk of dying from CVD independent of other clinical risk factors. Our findings underscored the importance of promoting CRF in the primary prevention of CVD in patients with hypercholesterolemia. [ABSTRACT FROM AUTHOR]

Objectives: We investigated whether high responsiveness or low responsiveness to exercise training aggregates in the same individuals across seven cardiometabolic traits.Methods: A total of 564 adults (29.2% black, 53.7% female) from the HERITAGE family study completed a 20-week endurance training programme (at 55%-75% of participants' maximal oxygen uptake (VO2max)) with VO2max, per cent body fat, visceral adipose tissue, fasting levels of insulin, high-density lipoprotein cholesterol, small low-density lipoprotein particles and inflammatory marker GlycA measured before and after training. For each exercise response trait, we created ethnicity-specific, sex-specific and generation-specific quintiles. High responses were defined as those within the 20th percentile representing the favourable end of the response trait distribution, low responses were defined as the 20th percentile from the least favourable end, and the remaining were labelled as average responses.Results: Only one individual had universally high or low responses for all seven cardiometabolic traits. Almost half (49%) of the cohort had at least one high response and one low response across the seven traits. About 24% had at least one high response but no low responses, 24% had one or more low responses but no high responses, and 2.5% had average responses across all traits.Conclusions: Interindividual variation in exercise responses was evident in all the traits we investigated, and responsiveness did not aggregate consistently in the same individuals. While adherence to an exercise prescription is known to produce health benefits, targeted risk factors may not improve. [ABSTRACT FROM AUTHOR]

Despite good adherence to supervised endurance exercise training (EET), some individuals experience no or little improvement in peripheral insulin sensitivity. The genetic and molecular mechanisms underlying this phenomenon are currently not understood. By investigating genome-wide variants associated with baseline and exercise-induced changes (∆) in insulin sensitivity index (Si) in healthy volunteers, we have identified novel candidate genes whose mouse knockouts phenotypes were consistent with a causative effect on Si. An integrative analysis of functional genomic and transcriptomic profiles suggests genetic variants have an aggregate effect on baseline Si and ∆Si, focused around cholinergic signalling, including downstream calcium and chemokine signalling. The identification of calcium regulated MEF2A transcription factor as the most statistically significant candidate driving the transcriptional signature associated to ∆Si further strengthens the relevance of calcium signalling in EET mediated Si response. [ABSTRACT FROM AUTHOR]

Disruptions to muscle protein turnover and metabolic regulation contribute to muscle wasting during the progression of cancer cachexia. The initiation of cachexia is also associated with decreased physical activity. While chronic muscle AMPK activation occurs during cachexia progression in ApcMin/+ (MIN) mice, a preclinical cachexia model, the understanding of muscle AMPK's role during cachexia initiation is incomplete. Therefore, we examined if voluntary wheel exercise could improve skeletal muscle AMPK signaling in pre‐cachectic MIN mice. Next, we examined muscle AMPK's role in aberrant catabolic signaling in response to a 12‐h fast in mice initiating cachexia. Male C57BL/6 (B6: N = 26) and MIN (N = 29) mice were subjected to ad libitum feeding, 12‐h fast, or 4 wks. of wheel access and then a 12‐h fast during the initiation of cachexia. Male tamoxifen‐inducible skeletal muscle AMPKα1α2 (KO) knockout mice crossed with ApcMin/+ and floxed controls were examined (WT: N = 8, KO: N = 8, MIN: N = 10, MIN KO: N = 6). Male mice underwent a 12‐h fast and the gastrocnemius muscle was analyzed. MIN gastrocnemius mass was reduced compared to B6 mice. A 12‐h fast induced MIN muscle AMPKT172, FOXOS413, and ULK‐1S555 phosphorylation compared to B6. Wheel running attenuated these inductions. A 12‐h fast induced MIN muscle MuRF‐1 protein expression compared to B6 and was suppressed by wheel running. Additionally, fasting induced muscle autophagy signaling and disrupted mitochondrial quality protein expression in the MIN, which was prevented in the MIN KO. We provide evidence that increased skeletal muscle AMPK sensitivity to a 12‐h fast is an adverse event in pre‐cachectic MIN mice, and exercise can improve this regulation. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine if offspring physical activity may affect the relationship between maternal overweight and offspring fatness and blood pressure (BP). Subjects included 144 maternal-child pairs (n = 74 boys and 70 girls, mean age = 7.3 yrs). Maternal prepregnancy BMI was determined by self-report. Offspring characteristics included resting systolic and diastolic BP, body fatness by dual energy x-ray absorbtiometry, and moderate-to-vigorous physical activity (MVPA) using the Actigraph accelerometer. Children whose mothers were overweight or obese prepregnancy (Prepreg OW) were significantly larger and fatter than children from mothers with a normal prepregnancy BMI (Prepreg NORM). Prepreg OW children also had higher mean arterial pressure than Prepreg NORM children. BP values were not different across maternal Prepreg BMI/ MVPA groups. Percent fat was significantly different across Prepreg BMI/MVPA groups. Prepreg OW children that did not meet the daily recommended value of MVPA were the fattest. Prepreg OW children that attained 360 min of MVPA/ day had a mean percent body fat that was similar to Prepreg NORM children of either MVPA group. [ABSTRACT FROM AUTHOR]

The present study examined the association between the angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism, physical activity, and resting blood pressure (BP) in a sample of 132 children (48.4% female). Children attaining 60 min/day of moderate-to-vigorous physical activity (MVPA) possessed lower % body fat (29% vs 24%, p < .05). Resting BP did not significantly differ between genotypes. Furthermore, partial correlations between MVPA and BP were low and did not vary by ACE genotype. Thus, the ACE I/D genotype is not associated with BP and does not modify the relationship between physical activity and BP in this sample of children. [ABSTRACT FROM AUTHOR]

There is evidence from human twin and family studies as well as mouse and rat selection experiments that there are considerable interindividual differences in the response of cardiorespiratory fitness (CRF) and other cardiometabolic traits to a given exercise programme dose. We developed this consensus statement on exercise response variability following a symposium dedicated to this topic. There is strong evidence from both animal and human studies that exercise training doses lead to variable responses. A genetic component contributes to exercise training response variability.In this consensus statement, we (1) briefly review the literature on exercise response variability and the various sources of variations in CRF response to an exercise programme, (2) introduce the key research designs and corresponding statistical models with an emphasis on randomised controlled designs with or without multiple pretests and post-tests, crossover designs and repeated measures designs, (3) discuss advantages and disadvantages of multiple methods of categorising exercise response levels-a topic that is of particular interest for personalised exercise medicine and (4) outline approaches that may identify determinants and modifiers of CRF exercise response. We also summarise gaps in knowledge and recommend future research to better understand exercise response variability. [ABSTRACT FROM AUTHOR]

Intrinsic cardiorespiratory fitness (CRF) is defined as the level of CRF in the sedentary state. There are large individual differences in intrinsic CRF among sedentary adults. The physiology of variability in CRF has received much attention, but little is known about the genetic and molecular mechanisms that impact intrinsic CRF. These issues were explored in the present study by interrogating intrinsic CRF-associated DNA sequence variation and skeletal muscle gene expression data from the HERITAGE Family Study through an integrative bioinformatics guided approach. A combined analytic strategy involving genetic association, pathway enrichment, tissue-specific network structure, cis-regulatory genome effects, and expression quantitative trait loci was used to select and rank genes through a variation-adjusted weighted ranking scheme. Prioritized genes were further interrogated for corroborative evidence from knockout mouse phenotypes and relevant physiological traits from the HERITAGE cohort. The mean intrinsic VO2max was 33.1 ml O2·kg-1·min-1 (SD = 8.8) for the sample of 493 sedentary adults. Suggestive evidence was found for gene loci related to cardiovascular physiology (ATE1, CASQ2, NOTO, and SGCG), hematopoiesis (PICALM, SSB, CA9, and CASQ2), skeletal muscle phenotypes (SGCG, DMRT2, ADARB1, and CASQ2), and metabolism (ATE1, PICALM, RAB11FIP5, GBA2, SGCG, PRADC1, ARL6IP5, and CASQ2). Supportive evidence for a role of several of these loci was uncovered via association between DNA variants and muscle gene expression levels with exercise cardiovascular and muscle physiological traits. This initial effort to define the underlying molecular substrates of intrinsic CRF warrants further studies based on appropriate cohorts and study designs, complemented by functional investigations. [ABSTRACT FROM AUTHOR]

Aim: Derangements in blood lipid and lipoprotein metabolism are one of the leading causes of coronary heart disease (CHD). Therapeutic lifestyle changes such as diet and exercise are often prescribed to improve blood lipid and lipoprotein characteristics, but the efficacy of a telephone‐based health coaching program has not been thoroughly explored. Our purpose was to examine effects of the Our Healthy Heart (OHH) Program on blood lipid and lipoprotein characteristics of individuals with mixed dyslipidaemia. Methods: Cholesterol content of serum very low‐density lipoprotein (VLDL), low‐density lipoprotein (LDL) and high‐density (HDL) subfractions and apolipoprotein concentrations were measured by vertical‐density ultracentrifugation (Vertical Auto Profile (VAP)) from 1522 individuals with mixed dyslipidaemia (age 18–99 years, body mass index (BMI) 25–40, 62.7% female). Telephone‐based health coaching (OHH, n = 722) or standard care (Control, n = 800) was provided for six months followed by VAP to evaluate changes in lipid and lipoprotein concentrations. Controls were obtained from individuals with similar blood lipid/lipoprotein characteristics who did not participate in the OHH Program. Coaches collected baseline self‐reported data on anthropometrics, food intake and exercise. Participants in the OHH group were then prescribed a hypocaloric 500 kcal/day caloric deficit with encouragement to participate in physical activity. A two‐way ANOVA was used to examine differences between groups over time, with results presented as means ± standard deviation. Results: Health coaching significantly decreased serum concentrations of apoB100 (104.5 ± 25.8–94.3 ± 24.8 mg/dL), shifted LDL pattern size from B to A or A/B in over 60% of the OHH group and decreased cholesterol content of all VLDL subfractions (P < 0.05) compared to the control. Conclusions: Telephone‐based health coaching recommendations to reduce dietary energy intake and increase physical activity produced significant improvements in cholesterol content of atherogenic lipoproteins, which are known to increase CHD risk. [ABSTRACT FROM AUTHOR]

Summary Regular endurance training improves muscle oxidative capacity and reduces the risk of age-related disorders. Understanding the molecular networks underlying this phenomenon is crucial. Here, by exploiting the power of computational modeling, we show that endurance training induces profound changes in gene regulatory networks linking signaling and selective control of translation to energy metabolism and tissue remodeling. We discovered that knockdown of the mTOR-independent factor Eif6 , which we predicted to be a key regulator of this process, affects mitochondrial respiration efficiency, ROS production, and exercise performance. Our work demonstrates the validity of a data-driven approach to understanding muscle homeostasis. [ABSTRACT FROM AUTHOR]

Predicting the responsiveness to regular exercise is a topic of great relevance due to its potential role in personalized exercise medicine applications. The present review focuses on cardiorespiratory fitness (commonly measured by maximal oxygen uptake [ABSTRACT FROM AUTHOR]

There are strong genetic components to cardiorespiratory fitness and its response to exercise training. It would be useful to understand the differences in the genomic profile of highly trained endurance athletes of world class caliber and sedentary controls. An international consortium (GAMES) was established in order to compare elite endurance athletes and ethnicity-matched controls in a case-control study design. Genome-wide association studies were undertaken on two cohorts of elite endurance athletes and controls (GENATHLETE and Japanese endurance runners), from which a panel of 45 promising markers was identified. These markers were tested for replication in seven additional cohorts of endurance athletes and controls: from Australia, Ethiopia, Japan, Kenya, Poland, Russia and Spain. The study is based on a total of 1520 endurance athletes (835 who took part in endurance events in World Championships and/or Olympic Games) and 2760 controls. We hypothesized that world-class athletes are likely to be characterized by an even higher concentration of endurance performance alleles and we performed separate analyses on this subsample. The meta-analysis of all available studies revealed one statistically significant marker (rs558129 at GALNTL6 locus, p = 0.0002), even after correcting for multiple testing. As shown by the low heterogeneity index (I2 = 0), all eight cohorts showed the same direction of association with rs558129, even though p-values varied across the individual studies. In summary, this study did not identify a panel of genomic variants common to these elite endurance athlete groups. Since GAMES was underpowered to identify alleles with small effect sizes, some of the suggestive leads identified should be explored in expanded comparisons of world-class endurance athletes and sedentary controls and in tightly controlled exercise training studies. Such studies have the potential to illuminate the biology not only of world class endurance performance but also of compromised cardiac functions and cardiometabolic diseases. [ABSTRACT FROM AUTHOR]

Aim: We performed genome-wide and transcriptome-wide profiling to identify genes and single nucleotide polymorphisms (SNPs) associated with the response of triglycerides (TG) to exercise training.Methods: Plasma TG levels were measured before and after a 20-week endurance training programme in 478 white participants from the HERITAGE Family Study. Illumina HumanCNV370-Quad v3.0 BeadChips were genotyped using the Illumina BeadStation 500GX platform. Affymetrix HG-U133+2 arrays were used to quantitate gene expression levels from baseline muscle biopsies of a subset of participants (N=52). Genome-wide association study (GWAS) analysis was performed using MERLIN, while transcriptomic predictor models were developed using the R-package GALGO.Results: The GWAS results showed that eight SNPs were associated with TG training-response (ΔTG) at p<9.9×10(-6), while another 31 SNPs showed p values <1×10(-4). In multivariate regression models, the top 10 SNPs explained 32.0% of the variance in ΔTG, while conditional heritability analysis showed that four SNPs statistically accounted for all of the heritability of ΔTG. A molecular signature based on the baseline expression of 11 genes predicted 27% of ΔTG in HERITAGE, which was validated in an independent study. A composite SNP score based on the top four SNPs, each from the genomic and transcriptomic analyses, was the strongest predictor of ΔTG (R(2)=0.14, p=3.0×10(-68)).Conclusions: Our results indicate that skeletal muscle transcript abundance at 11 genes and SNPs at a number of loci contribute to TG response to exercise training. Combining data from genomics and transcriptomics analyses identified a SNP-based gene signature that should be further tested in independent samples. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) prevalence in the United States is significantly higher in African Americans vs Whites. Yet, the physiological mechanisms contributing to this health disparity have been poorly described. To design effective strategies to reduce this disparity, there is a need to determine whether racial differences in diabetes prevalence are attributable to modifiable or non-modifiable factors. This review synthesizes and critically evaluates the potential physiological and genetic mechanisms that may contribute to the higher susceptibility of African Americans to T2D. These mechanisms include: 1) obesity and fat distribution; 2) metabolic flexibility; 3) muscle physiology; 4) energy expenditure and fitness; and 5) genetics. We focus on the clinical significance of findings and limitations of the recent literature. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) prevalence in the United States is significantly higher in African Americans vs Whites. Yet, the physiological mechanisms contributing to this health disparity have been poorly described. To design effective strategies to reduce this disparity, there is a need to determine whether racial differences in diabetes prevalence are attributable to modifiable or non-modifiable factors. This review synthesizes and critically evaluates the potential physiological and genetic mechanisms that may contribute to the higher susceptibility of African Americans to T2D. These mechanisms include: 1) obesity and fat distribution; 2) metabolic flexibility; 3) muscle physiology; 4) energy expenditure and fitness; and 5) genetics. We focus on the clinical significance of findings and limitations of the recent literature. [ABSTRACT FROM AUTHOR]

We previously reported the findings from a genome-wide association study of the response of maximal oxygen uptake (Vo2max) to an exercise program. Here we follow up on these results to generate hypotheses on genes, pathways, and systems involved in the ability to respond to exercise training. A systems biology approach can help us better establish a comprehensive physiological description of what underlies Vo2max trainability. The primary material for this exploration was the individual single-nucleotide polymorphism (SNP), SNP-gene mapping, and statistical significance levels. We aimed to generate novel hypotheses through analyses that go beyond statistical association of single-locus markers. This was accomplished through three complementary approaches: 1) building de novo evidence of gene candidacy through informatics-driven literature mining; 2) aggregating evidence from statistical associations to link variant enrichment in biological pathways to Vo2max trainability; and 3) predicting possible consequences of variants residing in the pathways of interest. We started with candidate gene prioritization followed by pathway analysis focused on overrepresentation analysis and gene set enrichment analysis. Subsequently, leads were followed using in silico analysis of predicted SNP functions. Pathways related to cellular energetics (pantothenate and CoA biosynthesis; PPAR signaling) and immune functions (complement and coagulation cascades) had the highest levels of SNP burden. In particular, long-chain fatty acid transport and fatty acid oxidation genes and sequence variants were found to influence differences in Vo2max trainability. Together, these methods allow for the hypothesis-driven ranking and prioritization of genes and pathways for future experimental testing and validation. [ABSTRACT FROM AUTHOR]

Context and Objective: Obesity and SLC2A9 genotype are strong determinants of uric acid levels. However, data on SLC2A9 variants and weight loss induced changes in uric acid levels are missing. We examined whether the changes in uric acid levels two- and ten-years after weight loss induced by bariatric surgery were associated with SLC2A9 single nucleotide polymorphisms (SNPs) in the Swedish Obese Subjects study. Methods: SNPs (N = 14) identified by genome-wide association studies and exonic SNPs in the SLC2A9 gene locus were genotyped. Cross-sectional associations were tested before (N = 1806), two (N = 1664) and ten years (N = 1201) after bariatric surgery. Changes in uric acid were compared between baseline and Year 2 (N = 1660) and years 2 and 10 (N = 1172). A multiple testing corrected threshold of P = 0.007 was used for statistical significance. Results: Overall, 11 of the 14 tested SLC2A9 SNPs were significantly associated with cross-sectional uric acid levels at all three time points, with rs13113918 showing the strongest association at each time point (R2 = 3.7-5.2%, 3.9×10-22⩽p⩽7.7×10-11). One SNP (rs737267) showed a significant association (R2 = 0.60%, P = 0.002) with change in uric acid levels from baseline to Year 2, as common allele homozygotes (C/C, N = 957) showed a larger decrease in uric acid (-61.4 μmol/L) compared to minor allele carriers (A/X: 251.7 μmol/L, N = 702). No SNPs were associated with changes in uric acid from years 2 to 10. Conclusions: SNPs in the SLC2A9 locus contribute significantly to uric acid levels in obese individuals, and the associations persist even after considerable weight loss due to bariatric surgery. However, we found little evidence for an interaction between genotype and weight change on the response of uric acid to bariatric surgery over ten years. Thus, the fluctuations in uric acid levels among the surgery group appear to be driven by the weight losses and gains, independent of SLC2A9 genotypes. [ABSTRACT FROM AUTHOR]

Although regular exercise improves submaximal aerobic capacity, there is large variability in its response to exercise training. While this variation is thought to be partly due to genetic differences, relatively little is known about the causal genes. Submaximal aerobic capacity traits in the current report include the responses of oxygen consumption (Δ VO60), power output (ΔWORK60), and cardiac output (ΔQ60) at 60% of VOmax to a standardized 20-week endurance exercise training program. Genome-wide linkage analysis in 475 HERITAGE Family Study Caucasians identified a locus on chromosome 13q for Δ VO60 (LOD = 3.11). Follow-up fine mapping involved a dense marker panel of over 1,800 single-nucleotide polymorphisms (SNPs) in a 7.9-Mb region (21.1-29.1 Mb from p-terminus). Single-SNP analyses found 14 SNPs moderately associated with both Δ VO60 at P ≤ 0.005 and the correlated traits of ΔWORK60 and ΔQ60 at P < 0.05. Haplotype analyses provided several strong signals ( P < 1.0 × 10) for Δ VO60. Overall, association analyses narrowed the target region and included potential biological candidate genes ( MIPEP and SGCG). Consistent with maximal heritability estimates of 23%, up to 20% of the phenotypic variance in Δ VO60 was accounted for by these SNPs. These results implicate candidate genes on chromosome 13q12 for the ability to improve submaximal exercise capacity in response to regular exercise. Submaximal exercise at 60% of maximal capacity is an exercise intensity that falls well within the range recommended in the Physical Activity Guidelines for Americans and thus has potential public health relevance. [ABSTRACT FROM AUTHOR]