A small number of excellent papers on exercise genomics issues have been 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 (BMI) 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. 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 ENCODE project.
Genetics; exercise training; physical activity; candidate genes; gene–exercise interaction; single nucleotide polymorphism; quantitative trait locus; genomic predictors
This review of the exercise genomics literature emphasizes the highest quality papers published in 2011. Given this emphasis on the best publications, only a small number of published papers are reviewed. One study found that physical activity levels were significantly lower in patients with mitochondrial DNA mutations compared to 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 (ACVR1B) 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 (GWAS) reports, on HDL-C. We conclude that a strong exercise genomics corpus of evidence would not only translate into powerful genomic predictors but would also have a major impact on exercise biology and exercise behavior research.
Genetics; exercise training; candidate genes; gene-exercise interaction; single nucleotide polymorphism; quantitative trait locus; genomic predictors
This review of the exercise genomics literature emphasizes the strongest papers 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 VO2max response to exercise training in one report from multiple laboratories. None of the 50 loci associated with adiposity traits is known to influence physical activity behavior. However, physical activity appears 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 following exposure to regular exercise. SNPs in the cAMP responsive element binding position 1 (CREB1) gene were associated with training-induced heart rate 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.
Genetics; exercise training; candidate genes; gene-exercise interaction; single nucleotide polymorphism; quantitative trait locus; genomic predictors
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.
Cardiovascular disease; inflammation; lipemia; metabolism
Insulin-like growth factor binding protein-1 (IGFBP-1) has metabolic effects throughout the body and its expression is regulated in part by insulin. Circulating IGFBP-1 predicts development of cardiometabolic diseases in longitudinal studies and low IGFBP-1 concentrations are associated with insulin resistance and consumption of a high-fat diet. Because of the favorable metabolic effects of regular aerobic exercise, we hypothesized that aerobic exercise training would increase plasma IGFBP-1 concentrations and attenuate the reduction in IGFBP-1 after a high-fat meal.
Ten overweight (BMI=28.7±0.9kg/m2), older (61±2yr) men and women underwent high-fat feeding and oral glucose tolerance tests (OGTT) at baseline and after 6 months of aerobic exercise training.
In response to aerobic exercise training, subjects increased cardiorespiratory fitness 13% (p<0.05) and insulin sensitivity index 28% (p<0.05). Basal plasma concentrations of IGFBP-1 increased 41% after aerobic exercise training (p<0.05). The insulin response to an OGTT was a significant predictor of fasting plasma IGFBP-1 concentrations at baseline and after exercise training (p=0.02). In response to the high-fat meal at baseline, plasma IGFBP-1 concentrations decreased 58% (p<0.001); a 61% decrease to similar postprandial concentrations was observed after exercise training (p<0.001). Plasma insulin response to the high-fat meal was inversely associated with postprandial IGFBP-1 concentrations at baseline and after exercise training (p=0.06 and p<0.05, respectively).
While aerobic exercise training did not attenuate the response to a high-fat meal, the increase in IGFBP-1 concentrations after exercise training may be one mechanism by which exercise reduces risk for cardiometabolic diseases in older adults.
insulin; glucose tolerance; lipemia; diet
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.
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.
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.
As part of the insulin signaling 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, 50-75 yr 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 measured percent body fat, computed tomography measured visceral and subcutaneous fat, and oral glucose tolerance testing measured glucose total area under the curve (AUC), insulin AUC, and insulin sensitivity. Taqman assay determined AKT1 G205T genotypes. At baseline, men with the GG genotype (n = 29) had lower VO2max values (p = 0.026), and higher percent 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 VO2max with training, the change in VO2max 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.
polymorphism; exercise; glucose
Fetuin-A is a liver-derived factor that may play a role in insulin resistance and age-related chronic diseases [e.g., type 2 diabetes and cardiovascular (CV) disease]. Regular exercise improves CV risk and insulin sensitivity, however it is unknown whether chronic exercise training is related to circulating levels of fetuin-A. Therefore, this study examined whether plasma fetuin-A levels were related to age and chronic physical activity in men. We hypothesized that chronic physical activity would be related to lower plasma fetuin-A levels in younger and older men. In healthy highly-active (HI) and low-active (LO) young (HI: n = 7; LO: n = 8) and older (HI: n = 12, LO: n = 11) men, we determined cardiorespiratory fitness (VO2max), plasma fetuin-A levels, plasma insulin, insulin resistance (HOMA-IR), and the standard risk factors for CV disease. Groups were matched for body mass index (BMI). Fetuin-A was significantly higher (∼20%) in both young and older LO men compared to their HI counterparts, and fetuin-A was inversely related to VO2max (r = -0.40, P = 0.014). Plasma fetuin-A levels showed trends to be significantly correlated with insulin (r = -0.34, P = 0.052) and HOMA-IR (r = 0.33, P = 0.058) in the older individuals. In younger participants, fetuin-A was related to blood pressure and cholesterol measures. These results indicate that low levels of fetuin-A are related to cardiorespiratory fitness and a number of conventional CV and metabolic disease risk factors independent of age and BMI. Therefore, the maintenance of low levels of circulating fetuin-A may be a novel mechanism contributing to enhanced insulin sensitivity with regular physical activity.
Fetuin-A; Exercise; Cardiovascular Disease; Diabetes; Insulin sensitivity
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 × PPP3R1 insertion-deletion (I/D) gene × 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 × 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.
genetics; muscle strength; muscle volume; muscle quality
To determine whether ethnicity interacts with the APO E genotype to influence conventionally-measured high density lipoprotein cholesterol (HDL-C) subfraction levels and Nuclear Magnetic Resonance measured (HDLNMR-C) particle size at baseline, after training, and changes with training.
After a 6-week dietary stabilization period, men and postmenopausal women 50-75 yrs old underwent baseline testing (NMR lipid, VO2max, body composition, and genotyping assessments). Tests were repeated after completing 24 wks of endurance exercise-training.
At baseline, APO E2/3 Blacks had significantly larger particle size (P<0.001) and higher total HDLNMR-C particle concentration (P=0.006) than Whites. After 6 months of endurance exercise-training, APO E2/3 Blacks maintained a significantly larger HDLNMR-C particle size (P<0.001), and particle concentration of the large HDLNMR-C than APO E2/3 Whites (P<0.001). In multivariate ANOVAs adjusted for demographic and environmental confounding factors, and training-induced changes in lean body mass and intra-abdominal fat; the model explained ∼33 percent of the observed variability in training-induced improvements in HDLNMR-C particle size (P=0.002), with APO E2/3 Blacks having a greater increase in training-induced changes in HDLNMR-C particle size. In a separate but similarly adjusted model for conventionally-measured HDL2-C, the model explained, ∼49 percent of the observed variability in training-induced changes in HDL2-C.
Ethnicity interacted with the E2/3 genotype at the APO E gene locus to influence higher baseline, after training, and greater exercise training-induced improvements in the advantageous HDL-C subfractions in Blacks than in Whites. APO E2/3 Blacks may benefit more from aerobic-fitness to reduce CVD risk.
Cholesterol; Genetics; Ethnicity; Exercise
The lectin-like ox-LDL receptor 1 (LOX-1) expressed on vascular cells plays a major role in atherogenesis by internalizing and degrading oxidized LDL. 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 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 to both the CT (p=0.02) and TT (p=0.002) genotype groups. Plasma sLOX-1 were also significantly higher in the 501GC genotype group compared to the GG genotype group (p=0.004). In univariate analyses, sLOX-1 levels were significantly associated with both the 3′UTR-C/T and G501 C polymorphisms. These associations remained significant after adjusting for age, gender, race, and BMI. In conclusion, variation in the LOX-1 gene is associated with plasma sLOX-1 levels in older men and women.
receptor; cardiovascular; gene expression
We investigated the association between soluble lectin-like oxidized LDL receptor 1 (sLOX-1) levels and obesity in older women. Fifty-one (10 lean, 22 overweight, and 19 obese) postmenopausal women were included in this small retrospective analysis. Plasma sLOX-1 levels were measured using a chemiluminescent ELISA. 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, HRT, and body fat. In conclusion, obese women have higher sLOX-1 levels, which may reflect increased LOX-1 expression in adipose tissue.
obesity; postmenopausal women; receptors
The goal of this study is to determine whether C-reactive protein (CRP) gene variants affect baseline and training-induced changes in plasma CRP levels.
Methods and Results
Sixty-three sedentary men and women aged 50 to 75 years old underwent baseline testing (VOmax, body composition, CRP levels). They repeated these tests after 24 weeks of exercise training while on a low-fat diet. The CRP +219G/A variant significantly associated with CRP levels before and after training after accounting for the effects of demographic and biological variables. CRP −732A/G genotype was significantly related on a univariate basis to CRP levels after training. The CRP +29T/A variant did not affect CRP levels before or after training. In regression analyses, the +219 and −732 variants each had significant effects on CRP levels before and after training. Subjects homozygous for the common A/G −732/+219 haplotype exhibited the highest CRP levels, and having the rare allele at either site was associated with significantly lower CRP levels. CRP levels decreased significantly with training (−0.38±0.18 mg/L; P=0.03). However, none of the CRP variants was associated with the training-induced CRP changes.
CRP +219G/A and −732A/G genotypes and haplotypes and exercise training appear to modulate CRP levels. However, training-induced CRP reductions appear to be independent of genotype at these loci.
C-reactive protein; genetics; exercise training
An etiologic role for chronic inflammation in the development of insulin resistance has been hypothesized. We determined whether the -732A/G and +219G/A C-reactive protein (CRP) gene variants affect insulin and glucose measures and whether these variants affect training-related changes in insulin sensitivity and glucose measures. Men and women 50 to 75 years old (n = 61) underwent baseline testing that included glucose tolerance, maximal oxygen consumption, body composition, CRP levels, and genotyping assessments. Tests were repeated after 24 weeks of aerobic exercise training. In bivariate analyses, CRP -732A/G G allele carriers had significantly lower baseline postprandial plasma glucose and after-training CRP levels. After exercise training, the -732A/G G allele carriers had ∼28% increase in insulin sensitivity index (ISI) and ∼26% reduction in insulin area under the curve (AUC), compared with the ∼7% increase in ISI and ∼15% reduction in insulin AUC in the A allele homozygotes ( P = .03). The significant enhancement of ISI in -732A/G G allele carriers remained evident in analyses limited to those with normal glucose tolerance. Multivariate analyses adjusted for demographic and biologic variables confirmed the significant enhancement of training-induced improvement in ISI by the CRP gene variant. In addition, the CRP -732A/G and +219G/A haplotype significantly associated with training-induced improvements in ISI and insulin AUC in separate multivariate models. In conclusion, the CRP -732A/G variant modulates exercise training—related improvements in ISI and glucose AUC, and the haplotype of the CRP -732A/G and +219G/A variants significantly affected training-induced changes in ISI and insulin AUC.
In endothelial cells, NF-κB 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-κ light-chain gene enhancer in B cells 1 (NFKB1) promoter polymorphism (−94NFKB1 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 −94NFKB1 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.
nuclear factor-κ light-chain gene enhancer in B cells 1; nitric oxide synthase 3; shear stress