Omics-driven investigation of the biology underlying intrinsic submaximal working capacity and its trainability.

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.

Regular exercise and patterns of response across multiple cardiometabolic traits: the HERITAGE family study.

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.

Effects of exercise on HDL functionality.

PURPOSE OF REVIEW: Low HDL-cholesterol (HDL-C) levels are a strong predictor of cardiovascular disease risk and can be improved with regular exercise. However, raising HDL-C levels pharmacologically has not shown convincing clinical benefits. Thus, research has recently focused on identifying therapies that improve HDL function, with exercise representing such a potential therapy. The purpose of this review is to summarize the effects of exercise interventions on HDL function. RECENT FINDINGS: The effects of exercise and lifestyle interventions on the primary atheroprotective functions of HDL are reviewed, namely, cholesterol efflux, antioxidative, and anti-inflammatory properties. Differences in study design, study population, and assays are discussed to aid in the interpretation of the reviewed studies. SUMMARY: There is mixed evidence that regular aerobic exercise improves cholesterol efflux capacity, with recent research suggesting an exercise dose threshold needs to be exceeded to produce beneficial effects. There is preliminary evidence that exercise improves the antioxidative and anti-inflammatory properties of HDL. Although exercise represents a potential therapeutic approach to improve HDL function, the heterogeneity and/or lack of findings warrants more and larger studies to determine what HDL function(s) are most responsive to regular exercise and what dose of exercise elicits the greatest improvements in HDL functionality.

Effects of Increasing Exercise Intensity and Dose on Multiple Measures of HDL (High-Density Lipoprotein) Function.

OBJECTIVE: Measures of HDL (high-density lipoprotein) function are associated with cardiovascular disease. However, the effects of regular exercise on these measures is largely unknown. Thus, we examined the effects of different doses of exercise on 3 measures of HDL function in 2 randomized clinical exercise trials. APPROACH AND RESULTS: Radiolabeled and boron dipyrromethene difluoride-labeled cholesterol efflux capacity and HDL-apoA-I (apolipoprotein A-I) exchange were assessed before and after 6 months of exercise training in 2 cohorts: STRRIDE-PD (Studies of Targeted Risk Reduction Interventions through Defined Exercise, in individuals with Pre-Diabetes; n=106) and E-MECHANIC (Examination of Mechanisms of exercise-induced weight compensation; n=90). STRRIDE-PD participants completed 1 of 4 exercise interventions differing in amount and intensity. E-MECHANIC participants were randomized into 1 of 2 exercise groups (8 or 20 kcal/kg per week) or a control group. HDL-C significantly increased in the high-amount/vigorous-intensity group (3±5 mg/dL; P=0.02) of STRRIDE-PD, whereas no changes in HDL-C were observed in E-MECHANIC. In STRRIDE-PD, global radiolabeled efflux capacity significantly increased 6.2% (SEM, 0.06) in the high-amount/vigorous-intensity group compared with all other STRRIDE-PD groups (range, -2.4 to -8.4%; SEM, 0.06). In E-MECHANIC, non-ABCA1 (ATP-binding cassette transporter A1) radiolabeled efflux significantly increased 5.7% (95% CI, 1.2-10.2%) in the 20 kcal/kg per week group compared with the control group, with no change in the 8 kcal/kg per week group (2.6%; 95% CI, -1.4 to 6.7%). This association was attenuated when adjusting for change in HDL-C. Exercise training did not affect BODIPY-labeled cholesterol efflux capacity or HDL-apoA-I exchange in either study. CONCLUSIONS: Regular prolonged vigorous exercise improves some but not all measures of HDL function. Future studies are warranted to investigate whether the effects of exercise on cardiovascular disease are mediated in part by improving HDL function. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT00962962 and NCT01264406.

Cardiovascular Health Trajectories and Elevated C-Reactive Protein: The CARDIA Study.

Background The relationship between long-term cardiovascular health (CVH) patterns and elevated CRP (C-reactive protein) in late middle age has yet to be investigated. We aimed to assess this relationship. Methods and Results Individual CVH components were measured in 4405 Black and White men and women (aged 18-30 years at baseline) in the CARDIA (Coronary Artery Risk Development in Young Adults) study at 8 examinations over 25 years. CRP was measured at 4 examinations (years 7, 15, 20, and 25). Latent class modeling was used to identify individuals with similar trajectories in CVH from young adulthood to middle age. Multivariable Poisson regression models were used to assess the association between race-specific CVH trajectories and prevalence of elevated CRP levels (>3.0 mg/L) after 25 years of follow-up. Five distinct CVH trajectories were identified for each race. Lower and decreasing trajectories had higher prevalence of elevated CRP relative to the highest trajectory. Prevalence ratios for elevated CRP in lowest trajectory groups at year 25 were 2.58 (95% CI, 1.89-3.51) and 7.20 (95% CI, 5.09-10.18) among Black and White people, respectively. Prevalence ratios for chronically elevated CRP (elevated CRP at 3 or more of the examinations) in the lowest trajectory groups were 8.37 (95% CI, 4.37-16.00) and 15.89 (95% CI, 9.01-28.02) among Black and White people, respectively. Conclusions Lower and decreasing CVH trajectories are associated with higher prevalence of elevated CRP during the transition from young adulthood to middle age.

Exploring the underlying biology of intrinsic cardiorespiratory fitness through integrative analysis of genomic variants and muscle gene expression profiling.

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 V̇o2max 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. NEW & NOTEWORTHY Intrinsic cardiorespiratory fitness (CRF) is measured in the sedentary state and is highly variable among sedentary adults. The physiology of variability in intrinsic cardiorespiratory fitness has received much attention, but little is known about the genetic and molecular mechanisms that impact intrinsic CRF. These issues were explored computationally in the present study, with further corroborative evidence obtained from analysis of phenotype data from knockout mouse models and human cardiovascular and skeletal muscle measurements.