The HERITAGE Family Study: A review of the effects of exercise training on cardiometabolic health, with insights into molecular transducers

The aim of the HERITAGE Family Study was to investigate individual differences in response to a standardized endurance exercise program, the role of familial aggregation, and the genetics of response levels of cardiorespiratory fitness and cardiovascular disease and diabetes risk factors. Here we summarize the findings and their potential implications for cardiometabolic health and cardiorespiratory fitness. It begins with overviews of background and planning, recruitment, testing and exercise program protocol, quality control measures, and other relevant organizational issues. A summary of findings is then provided on cardiorespiratory fitness, exercise hemodynamics, insulin and glucose metabolism, lipid and lipoprotein profiles, adiposity and abdominal visceral fat, blood levels of steroids and other hormones, markers of oxidative stress, skeletal muscle morphology and metabolic indicators, and resting metabolic rate. These summaries document the extent of the individual differences in response to a standardized and fully monitored endurance exercise program and document the importance of familial aggregation and heritability level for exercise response traits. Findings from genomic markers, muscle gene expression studies, and proteomic and metabolomics explorations are reviewed, along with lessons learned from a bioinformatics-driven analysis pipeline. The new opportunities being pursued in integrative -omics and physiology have extended considerably the expected life of HERITAGE and are being discussed in relation to the original conceptual model of the study

Examination of the Prevalence of Female Athlete Triad Components among Competitive Cheerleaders

The purpose of this study was to examine individual and combined Female Athlete Triad components within collegiate cheerleaders, an at-risk group. Cheerleaders ( = 19; age: 20.3 ± 1.2 years) completed anthropometric measurements, health history questionnaires, resting metabolic rate, the eating disorder inventory-3 and symptom checklist, blood sample, and DXA scan. Participants completed dietary and exercise logs for 7 days and used heart rate monitors to track daily and exercise energy expenditure. Proportions were calculated for low energy availability (LEA) risk, disordered eating risk, and pathogenic behaviors. Chi-square analysis was used to determine the difference between cheerleaders who experience low EA with or without disordered eating risk. All cheerleaders demonstrated LEA for the days they participated in cheerleading practice, 52.6% demonstrated LEA with eating disorder risk and 47.4% demonstrated LEA without eating disorder risk, 52.6% self-reported menstrual dysfunction, 14% experienced menstrual dysfunction via hormonal assessment, and 0% demonstrated low bone mineral density. Overall, 47.7% presented with one Triad component, 52.6% demonstrated two Triad components using self-reported menstrual data, and 10.5% demonstrated two Triad components using hormonal assessments. All cheerleaders displayed LEA. These findings support the need for increased education on the individual components of the Triad and their potential consequences by qualified personal

Investigation of Eating Disorder Risk and Body Image Dissatisfaction among Female Competitive Cheerleaders

Social agents associated with cheerleading environments are increasingly linked to body image dissatisfaction (BID) and eating disorders (ED). This study examined ED risk across team type, squad type, and position. An additional purpose determined BID in clothing type (daily clothing, midriff uniform, and full uniform), and meta-perceptions from the perspective of peers (MP peers), parents (MP parents), and coaches (MP coaches). Female cheerleaders ( = 268) completed an online survey which included demographics, the Eating Attitudes Test-26, and pathogenic behavior questions. Body image perceptions were assessed by using the Sex-Specific Figural Stimuli Silhouettes. Overall, 34.4% of cheerleaders ( = 268; mean age: 17.9 ± 2.7 years) exhibited an ED risk. Compared to All-Star cheerleaders, college cheerleaders demonstrated significant higher ED risk ( = 0.021), dieting subscale scores ( = 0.045), and laxative, diet pill, and diuretic use ( = 0.008). Co-ed teams compared to all-girl teams revealed higher means for the total EAT-26 ( = 0.018) and oral control subscale ( = 0.002). The BID in clothing type revealed that cheerleaders wanted to be the smallest in the midriff option ( \u3c 0.0001, η2 = 0.332). The BID from meta-perception revealed that cheerleaders felt that their coaches wanted them to be the smallest ( \u3c 0.001, η2 = 0.106). Cheerleaders are at risk for EDs and BID at any level. Regarding the midriff uniform, MP from the perspective of coaches showed the greatest difference between perceived and desired body image

The impact of cardiorespiratory fitness levels on the risk of developing atherogenic dyslipidemia

Background Low cardiorespiratory fitness has been established as a risk factor for cardiovascular-related morbidity. However, research about the impact of fitness on lipid abnormalities, including atherogenic dyslipidemia, has produced mixed results. The purpose of this investigation is to examine the influence of baseline fitness and changes in fitness on the development of atherogenic dyslipidemia. Methods All participants completed at least 3 comprehensive medical examinations performed by a physician that included a maximal treadmill test between 1976 and 2006 at the Cooper Clinic in Dallas, Texas. Atherogenic dyslipidemia was defined as a triad of lipid abnormalities: low high-density-lipoprotein cholesterol ([HDL-C

Wheel Running Improves Fasting-Induced AMPK Signaling in Skeletal Muscle From Tumor-Bearing Mice

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

Changes in cardiorespiratory fitness following exercise training prescribed relative to traditional intensity anchors and to physiological thresholds: a systematic review with meta-analysis of individual participant data.

It is unknown whether there are differences in maximal oxygen uptake (VO2max) response when prescribing intensity relative to traditional (TRAD) anchors or to physiological thresholds (THR). The present meta-analysis sought to compare: a) mean change in VO2max; b) proportion of individuals increasing VO2max beyond a minimum important difference (MID); and c) response variability in VO2max between TRAD and THR. Electronic databases were searched, yielding data for 1544 individuals from 42 studies. Two datasets were created, comprising studies with a control group ('controlled' studies), and without a control group ('non-controlled' studies). A Bayesian approach with multi-level distributional models was used to separately analyse VO2max change scores from the two datasets and inferences were made using Bayes factors (BF). The MID was predefined as one metabolic equivalent (MET; 3.5 mL∙kg-1∙min-1). In controlled studies, mean VO2max change was greater in THR compared to TRAD (4.1 vs 1.8 mL∙kg-1∙min-1, BF>100) with 64% of individuals in THR experiencing an increase in VO2max >MID, compared to 16% of individuals taking part in TRAD. Evidence indicated no difference in standard deviation of change between THR and TRAD (1.5 vs 1.7 mL∙kg-1∙min-1, BF=0.55), and greater variation in exercise groups relative to non-exercising controls (1.9 vs 1.3 mL∙kg-1∙min-1, BF=12.4). In non-controlled studies, mean VO2max change was greater in THR vs TRAD (4.4 vs 3.4 mL∙kg-1∙min-1, BF=35.1) with no difference in standard deviation of change (3.0 vs 3.2 mL∙kg-1∙min-1, BF=0.41). Prescribing exercise intensity using THR approaches elicited superior mean changes in VO2max and increased the likelihood of increasing VO2max beyond the MID compared to TRAD. Future exercise training studies should thus consider the use of THR approaches to prescribe exercise intensity where possible. Analysis comparing interventions with controls suggested the existence of intervention response heterogeneity, however, evidence was not obtained for a difference in response variability between THR and TRAD. Future primary research should be conducted with adequate power to investigate the scope of inter-individual differences in VO2max trainability, and if meaningful, the causative factors

Proteomic Profiling Platforms Head to Head: Leveraging Genetics and Clinical Traits to Compare Aptamer- And Antibody-Based Methods

High-throughput proteomic profiling using antibody or aptamer-based affinity reagents is used increasingly in human studies. However, direct analyses to address the relative strengths and weaknesses of these platforms are lacking. We assessed findings from the SomaScan1.3K (N = 1301 reagents), the SomaScan5K platform (N = 4979 reagents), and the Olink Explore (N = 1472 reagents) profiling techniques in 568 adults from the Jackson Heart Study and 219 participants in the HERITAGE Family Study across four performance domains: precision, accuracy, analytic breadth, and phenotypic associations leveraging detailed clinical phenotyping and genetic data. Across these studies, we show evidence supporting more reliable protein target specificity and a higher number of phenotypic associations for the Olink platform, while the Soma platforms benefit from greater measurement precision and analytic breadth across the proteome

Investigation of Eating Disorder Risk and Body Image Dissatisfaction Among Female Competitive Cheerleaders

Social agents associated with cheerleading environments are increasingly linked to body image dissatisfaction (BID) and eating disorders (ED). This study examined ED risk across team type, squad type, and position. An additional purpose determined BID in clothing type (daily clothing, midriff uniform, and full uniform), and meta-perceptions from the perspective of peers (MP peers), parents (MP parents), and coaches (MP coaches). Female cheerleaders (n = 268) completed an online survey which included demographics, the Eating Attitudes Test-26, and pathogenic behavior questions. Body image perceptions were assessed by using the Sex-Specific Figural Stimuli Silhouettes. Overall, 34.4% of cheerleaders (n = 268; mean age: 17.9 ± 2.7 years) exhibited an ED risk. Compared to All-Star cheerleaders, college cheerleaders demonstrated significant higher ED risk (p = 0.021), dieting subscale scores (p = 0.045), and laxative, diet pill, and diuretic use (p = 0.008). Co-ed teams compared to all-girl teams revealed higher means for the total EAT-26 (p = 0.018) and oral control subscale (p = 0.002). The BID in clothing type revealed that cheerleaders wanted to be the smallest in the midriff option (p \u3c 0.0001, η2 = 0.332). The BID from meta-perception revealed that cheerleaders felt that their coaches wanted them to be the smallest (p \u3c 0.001, η2 = 0.106). Cheerleaders are at risk for EDs and BID at any level. Regarding the midriff uniform, MP from the perspective of coaches showed the greatest difference between perceived and desired body image

No Evidence of a Common DNA Variant Profile Specific to World Class Endurance Athletes

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

Protein-metabolite association studies identify novel proteomic determinants of metabolite levels in human plasma

Although many novel gene-metabolite and gene-protein associations have been identified using high-throughput biochemical profiling, systematic studies that leverage human genetics to illuminate causal relationships between circulating proteins and metabolites are lacking. Here, we performed protein-metabolite association studies in 3,626 plasma samples from three human cohorts. We detected 171,800 significant protein-metabolite pairwise correlations between 1,265 proteins and 365 metabolites, including established relationships in metabolic and signaling pathways such as the protein thyroxine-binding globulin and the metabolite thyroxine, as well as thousands of new findings. In Mendelian randomization (MR) analyses, we identified putative causal protein-to-metabolite associations. We experimentally validated top MR associations in proof-of-concept plasma metabolomics studies in three murine knockout strains of key protein regulators. These analyses identified previously unrecognized associations between bioactive proteins and metabolites in human plasma. We provide publicly available data to be leveraged for studies in human metabolism and disease