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

Genome-wide association studies suggest sex-specific loci associated with abdominal and visceral fat

Background: To identify loci associated with abdominal fat and replicate prior findings, we performed genome-wide association (GWA) studies of abdominal fat traits: subcutaneous adipose tissue (SAT); visceral adipose tissue (VAT); total adipose tissue (TAT) and visceral to subcutaneous adipose tissue ratio (VSR). Subjects and Methods: Sex-combined and sex-stratified analyses were performed on each trait with (TRAIT–BMI) or without (TRAIT) adjustment for body mass index (BMI), and cohort-specific results were combined via a fixed effects meta-analysis. A total of 2513 subjects of European descent were available for the discovery phase. For replication, 2171 European Americans and 772 African Americans were available. Results: A total of 52 single-nucleotide polymorphisms (SNPs) encompassing 7 loci showed suggestive evidence of association (P\u3c1.0 × 10−6) with abdominal fat in the sex-combined analyses. The strongest evidence was found on chromosome 7p14.3 between a SNP near BBS9 gene and VAT (rs12374818; P=1.10 × 10−7), an association that was replicated (P=0.02). For the BMI-adjusted trait, the strongest evidence of association was found between a SNP near CYCSP30 and VAT–BMI (rs10506943; P=2.42 × 10−7). Our sex-specific analyses identified one genome-wide significant (P\u3c5.0 × 10−8) locus for SAT in women with 11 SNPs encompassing the MLLT10, DNAJC1 and EBLN1 genes on chromosome 10p12.31 (P=3.97 × 10–8 to 1.13 × 10−8). The THNSL2 gene previously associated with VAT in women was also replicated (P=0.006). The six gene/loci showing the strongest evidence of association with VAT or VAT-BMI were interrogated for their functional links with obesity and inflammation using the Biograph knowledge-mining software. Genes showing the closest functional links with obesity and inflammation were ADCY8 and KCNK9, respectively. Conclusions: Our results provide evidence for new loci influencing abdominal visceral (BBS9, ADCY8, KCNK9) and subcutaneous (MLLT10/DNAJC1/EBLN1) fat, and confirmed a locus (THNSL2) previously reported to be associated with abdominal fat in women

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

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

Precision exercise medicine: understanding exercise response variability

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 variability531811411153The consensus meeting that led to the writing of this manuscript was held with the financial support of the Pennington Biomedical Research Foundation, the Pennington Biomedical Research Center Division of Education, the LSU Boyd Professorship and the John W. Barton, Sr. Chair in Genetics and Nutrition. No funding and/or honorarium was provided to any member of the writing group for the production of this manuscrip

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

The Role of Eif6 in Skeletal Muscle Homeostasis Revealed by Endurance Training Co-expression Networks

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

Solar Energy: Incentives to Promote PV in EU27

The growth in the use of renewable energies in the EU has been remarkable. Among these energies is PV. The average annual growth rate for the EU-27 countries in installed PV capacity in the period 2005-2012 was 41.2%. While the installed capacity of PV has reached almost 82 % of National Renewable Energy Action Plan (NREAP) targets for the EU-27 countries for 2020, it is still far from being used at its full potential. Over recent years, several measures have been adopted in the EU to enhance and promote PV. This paper undertakes a complete review of the state of PV power in Europe and the measures taken to date to promote it in EU-27. 25 countries have adopted measures to promote PV. The most widespread measure to promote PV use is Feed- in Tariffs. Tariffs are normally adjusted, in a decreasing manner, annually. Nevertheless, currently, seven countries have decided to accelerate this decrease rate in view of cost reduction of the installations and of higher efficiencies. The second instrument used to promote PV in the EU-27 countries is the concession of subsidies. Nevertheless, subsidies have the disadvantage of being closely linked to budgetary resources and therefore to budgetary constraints. In most EU countries, subsidies for renewable energy for PV are being lowered. Twelve EU-27 countries adopted tax measures. Low-interest loans and green certificate systems were only sparingly used

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