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Background: It is unknown whether there are differences in maximal oxygen uptake ( V O 2max ) response when prescribing intensity relative to traditional (TRAD) anchors or to physiological thresholds (THR)., Objectives: The present meta-analysis sought to compare: (a) mean change in V O 2max , (b) proportion of individuals increasing V O 2max beyond a minimum important difference (MID) and (c) response variability in V O 2max between TRAD and THR., Methods: 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 V O 2max 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 )., Results: In controlled studies, mean V O 2max change was greater in the THR group compared with TRAD (4.1 versus 1.8 mL kg -1  min -1 , BF > 100), with 64% of individuals in the THR group experiencing an increase in V O 2max  > MID, compared with 16% of individuals taking part in TRAD. Evidence indicated no difference in standard deviation of change between THR and TRAD (1.5 versus 1.7 mL kg -1  min -1 , BF = 0.55), and greater variation in exercise groups relative to non-exercising controls (1.9 versus 1.3 mL kg -1  min -1 , BF = 12.4). In non-controlled studies, mean V O 2max change was greater in the THR group versus the TRAD group (4.4 versus 3.4 mL kg -1  min -1 , BF = 35.1), with no difference in standard deviation of change (3.0 versus 3.2 mL kg -1  min -1 , BF = 0.41)., Conclusion: Prescribing exercise intensity using THR approaches elicited superior mean changes in V O 2max and increased the likelihood of increasing V O 2max beyond the MID compared with TRAD. Researchers designing 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 V O 2max trainability, and if meaningful, the causative factors., Competing Interests: Declarations Funding No funding and financial assistance was used for this review. Conflicts of Interest Authors Samuel J. R. Meyler, Paul A. Swinton, Lindsay Bottoms, Lance C. Dalleck, Ben Hunter, Mark A. Sarzynski, David Wellsted, Camilla J. Williams and Daniel Muniz-Pumares declare that they have no conflicts of interest relevant to the content of this review. Availability of Data and Material Datasets analysed in the current review are available upon reasonable request but are subject to permission from original authors. Ethics Approval Each study received ethical approval from their respective institutions, conformed to the guidelines of the Declaration of Helsinki and obtained written informed consent from each participant prior to commencing data collection. Author Contributions All authors: (1) made substantial contributions to the conception or design of the work or to the acquisition, analysis, or interpretation of data and (2) drafted the work or revised it critically for important intellectual content. All authors read and approved the final version of the manuscript., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The goal of this study was to examine the relationship between diet quality, nutrients, and health outcomes among participants in the Dietary Guidelines: 3 Diets study (3-group randomized 12-week intervention; African American; Southeastern virtual teaching kitchen). Participants (n = 63; ages 18-65 y, BMI 25-49.9 kg/m 2 ) were randomized to the Healthy U.S. (H-US), Mediterranean (Med), or Vegetarian (Veg) groups. Hypotheses tested included (1) that the more plant-based diet patterns (Veg and Med) would have greater improvements in all diet quality indices (Dietary Approaches to Stop Hypertension (DASH), Dietary Inflammatory Index (DII), alternate Mediterranean Diet Index (aMED), healthy Plant-based Dietary Index (hPDI) assessed via three dietary recalls) as compared to the H-US pattern and (2) that each index would separately predict changes in weight loss, hemoglobin A1c (HbA1c), and blood pressure (BP). None of the group-by-time interactions for any of the diet indices were significant. Compared to the H-US group, Veg participants had greater increases in fiber (difference between groups 5.72 ± 2.10 5 g/day; P = .01), riboflavin (0.38 ± 0.19 mg/day; P = .05), and folate (87.39 ± 40.36 mcg/day; P = .03). For every one-point increase in hPDI, there was a 1.62 ± 0.58 mmHg decrease in systolic BP, for every one-point increase in aMED there was a 1.45 ± 0.70 mmHg decrease in diastolic BP, and for every one-point increase in hPDI, there was a 1.15 ± 0.38 mmHg decrease in diastolic BP. Findings indicate that there is significant overlap in the dietary recommendations of the three dietary patterns presented in the USDG and similarities in how African American adults adopt those diet patterns. Clinical Trials registry at clinicaltrials.gov:NCT04981847., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: ANGPTL3/4/8 (angiopoietin-like proteins 3, 4, and 8) are important regulators of LPL (lipoprotein lipase). ANGPTL8 forms complexes with ANGPTL3 and ANGPTL4. ANGPTL4/8 complex formation converts ANGPTL4 from a furin substrate to a plasmin substrate, and both cleavages generate similar C-terminal domain-containing (CD)-ANGPTL4 fragments. Whereas several studies have investigated associations of free ANGPTL proteins with cardiovascular risk, there are no data describing associations of the complexes and CD-ANGPTL4 with outcomes or describing the effects of the complexes on LPL bound to GPIHBP1 (glycosylphosphatidylinositol HDL-binding protein 1)., Methods: Recombinant protein assays were used to study ANGPTL protein and complex effects on GPIHBP1-LPL activity. ANGPTL3/8, ANGPTL3, ANGPTL4/8, and CD-ANGPTL4 were measured with dedicated immunoassays in 2394 LURIC (Ludwigshafen Risk and Cardiovascular Health) study participants undergoing coronary angiography and 6188 getABI study (German Epidemiological Trial on Ankle Brachial Index) participants undergoing ankle brachial index measurement. There was a follow-up for cardiovascular death with a median (interquartile range) duration of 9.80 (8.75-10.40) years in the LURIC study and 7.06 (7.00-7.14) years in the getABI study., Results: ANGPTL3/8 potently inhibited GPIHBP1-LPL activity and showed positive associations with LDL-C (low-density lipoprotein cholesterol) and triglycerides (both P <0.001). However, in neither study did ANGPTL3/8 correlate with cardiovascular death. Free ANGPTL3 was positively associated with cardiovascular death in the getABI study but not the LURIC study. ANGPTL4/8 and especially CD-ANGPTL4 were positively associated with the prevalence of diabetes, CRP (C-reactive protein; all P <0.001), and cardiovascular death in both studies. In the LURIC and getABI studies, respective hazard ratios for cardiovascular mortality comparing the third with the first ANGPTL4/8 tertile were 1.47 (1.15-1.88) and 1.68 (1.25-2.27) when adjusted for sex, age, body mass index, and diabetes. For CD-ANGPTL4, these hazard ratios were 2.44 (1.86-3.20) and 2.76 (2.00-3.82)., Conclusions: ANGPTL3/8 potently inhibited GPIHBP1-LPL enzymatic activity, consistent with its positive association with serum lipids. However, ANGPTL3/8, LDL-C, and triglyceride levels were not associated with cardiovascular death in the LURIC and getABI cohorts. In contrast, concentrations of ANGPTL4/8 and particularly CD-ANGPTL4 were positively associated with inflammation, the prevalence of diabetes, and cardiovascular mortality.

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.

Background and Aims: Previous studies have derived and validated an HDL apolipoproteomic score (pCAD) that predicts coronary artery disease (CAD) risk. However, the associations between pCAD and markers of cardiometabolic health in healthy adults are not known, nor are the effects of regular exercise on pCAD., Methods: A total of 641 physically inactive adults free of cardiovascular disease from the HERITAGE Family Study completed 20 weeks of exercise training. The pCAD index (range 0-100) was calculated using measurements of apolipoproteins A-I, C-I, C-II, C-III, and C-IV from ApoA-I-tagged serum (higher index = higher CAD risk). The associations between pCAD index and cardiometabolic traits at baseline and their training responses were assessed with Spearman correlation and general linear models. A Bonferroni correction of p < 8.9 × 10 -04 was used to determine statistical significance., Results: The mean ± SD baseline pCAD index was 29 ± 32, with 106 (16.5 %) participants classified as high CAD risk. At baseline, pCAD index was positively associated with blood pressure, systemic inflammation, and body composition. HDL size, VO 2 max, and HDL-C were negatively associated with pCAD index at baseline. Of those classified as high CAD risk at baseline, 52 (49 %) were reclassified as normal risk after training. Following training, pCAD index changes were inversely correlated (p < 1.4 × 10 -04 ) with changes in HDL-C, HDL size, and LDL size., Conclusions: A higher pCAD index was associated with a worse cardiometabolic profile at baseline but improved with regular exercise. The results from this study highlight the potential role of HDL apolipoproteins as therapeutic targets for lifestyle interventions, particularly in high-risk individuals., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mark A. Sarzynski reports financial support was provided by National Institutes of Health. Robert E. Gerszten reports a relationship with National Institutes of Health that includes: funding grants. J. Sebastian Miranda Maravi reports a relationship with National Institutes of Health that includes: funding grants. Jacob L. Barber reports a relationship with National Institutes of Health that includes: funding grants. Ryan W. Pearce reports a relationship with Quest Diagnostics that includes: employment and equity or stocks. Michael J. McPhaul reports a relationship with Quest Diagnostics that includes: employment and equity or stocks. Timothy S. Collier reports a relationship with Quest Diagnostics that includes: employment and equity or stocks. Robert J. Konrad reports a relationship with Eli Lilly and Company that includes: employment and equity or stocks. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Importance: Blood pressure response during acute exercise (exercise blood pressure [EBP]) is associated with the future risk of hypertension and cardiovascular disease (CVD). Biochemical characterization of EBP could inform disease biology and identify novel biomarkers of future hypertension., Objective: To identify protein markers associated with EBP and test their association with incident hypertension., Design, Setting, and Participants: This study assayed 4977 plasma proteins in 681 healthy participants (from 763 assessed) of the Health, Risk Factors, Exercise Training and Genetics (HERITAGE; data collection from January 1993 to December 1997 and plasma proteomics from January 2019 to January 2020) Family Study at rest who underwent 2 cardiopulmonary exercise tests. Individuals were free of CVD at the time of recruitment. Individuals with resting SBP ≥160 mm Hg or DBP ≥100 mm Hg or taking antihypertensive drug therapy were excluded from the study. The association between resting plasma protein levels to both resting BP and EBP was evaluated. Proteins associated with EBP were analyzed for their association with incident hypertension in the Framingham Heart Study (FHS; n = 1177) and validated in the Jackson Heart Study (JHS; n = 772) and Multi-Ethnic Study of Atherosclerosis (MESA; n = 1367). Proteins associated with incident hypertension were tested for putative causal links in approximately 700 000 individuals using cis-protein quantitative loci mendelian randomization (cis-MR). Data were analyzed from January 2023 to January 2024., Exposures: Plasma proteins., Main Outcomes and Measures: EBP was defined as the BP response during a fixed workload (50 W) on a cycle ergometer. Hypertension was defined as BP ≥140/90 mm Hg or taking antihypertensive medication., Results: Among the 681 participants in the HERITAGE Family Study, the mean (SD) age was 34 (13) years; 366 participants (54%) were female; 238 (35%) were self-reported Black and 443 (65%) were self-reported White. Proteomic profiling of EBP revealed 34 proteins that would not have otherwise been identified through profiling of resting BP alone. Transforming growth factor β receptor 3 (TGFBR3) and prostaglandin D2 synthase (PTGDS) had the strongest association with exercise systolic BP (SBP) and diastolic BP (DBP), respectively (TGFBR3: exercise SBP, β estimate, -3.39; 95% CI, -4.79 to -2.00; P = 2.33 × 10-6; PTGDS: exercise DBP β estimate, -2.50; 95% CI, -3.29 to -1.70; P = 1.18 × 10-9). In fully adjusted models, TGFBR3 was inversely associated with incident hypertension in FHS, JHS, and MESA (hazard ratio [HR]: FHS, 0.86; 95% CI, 0.75-0.97; P = .01; JHS, 0.87; 95% CI, 0.77-0.97; P = .02; MESA, 0.84; 95% CI, 0.71-0.98; P = .03; pooled cohort, 0.86; 95% CI, 0.79-0.92; P = 6 × 10-5). Using cis-MR, genetically predicted levels of TGFBR3 were associated with SBP, hypertension, and CVD events (SBP: β, -0.38; 95% CI, -0.64 to -0.11; P = .006; hypertension: odds ratio [OR], 0.99; 95% CI, 0.98-0.99; P < .001; heart failure with hypertension: OR, 0.86; 95% CI, 0.77-0.97; P = .01; CVD: OR, 0.84; 95% CI, 0.77-0.92; P = 8 × 10-5; cerebrovascular events: OR, 0.77; 95% CI, 0.70-0.85; P = 5 × 10-7)., Conclusions and Relevance: Plasma proteomic profiling of EBP identified a novel protein, TGFBR3, which may protect against elevated BP and long-term CVD outcomes.

Despite the wide effects of cardiorespiratory fitness (CRF) on metabolic, cardiovascular, pulmonary and neurological health, challenges in the feasibility and reproducibility of CRF measurements have impeded its use for clinical decision-making. Here we link proteomic profiles to CRF in 14,145 individuals across four international cohorts with diverse CRF ascertainment methods to establish, validate and characterize a proteomic CRF score. In a cohort of around 22,000 individuals in the UK Biobank, a proteomic CRF score was associated with a reduced risk of all-cause mortality (unadjusted hazard ratio 0.50 (95% confidence interval 0.48-0.52) per 1 s.d. increase). The proteomic CRF score was also associated with multisystem disease risk and provided risk reclassification and discrimination beyond clinical risk factors, as well as modulating high polygenic risk of certain diseases. Finally, we observed dynamicity of the proteomic CRF score in individuals who undertook a 20-week exercise training program and an association of the score with the degree of the effect of training on CRF, suggesting potential use of the score for personalization of exercise recommendations. These results indicate that population-based proteomics provides biologically relevant molecular readouts of CRF that are additive to genetic risk, potentially modifiable and clinically translatable., (© 2024. The Author(s).)

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., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Samani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Angiopoietin-like protein (ANGPTL) complexes 3/8 and 4/8 are established inhibitors of LPL and novel therapeutic targets for dyslipidemia. However, the effects of regular exercise on ANGPTL3/8 and ANGPTL4/8 are unknown. We characterized ANGPTL3/8 and ANGPTL4/8 and their relationship with in vivo measurements of lipase activities and cardiometabolic traits before and after a 5-month endurance exercise training intervention in 642 adults from the HERITAGE (HEalth, RIsk factors, exercise Training And GEnetics) Family Study. At baseline, higher levels of both ANGPTL3/8 and ANGPTL4/8 were associated with a worse lipid, lipoprotein, and cardiometabolic profile, with only ANGPTL3/8 associated with postheparin LPL and HL activities. ANGPTL3/8 significantly decreased with exercise training, which corresponded with increases in LPL activity and decreases in HL activity, plasma triglycerides, apoB, visceral fat, and fasting insulin (all P < 5.1 × 10 -4 ). Exercise-induced changes in ANGPTL4/8 were directly correlated to concomitant changes in total cholesterol, LDL-C, apoB, and HDL-triglycerides and inversely related to change in insulin sensitivity index (all P < 7.0 × 10 -4 ). In conclusion, exercise-induced decreases in ANGPTL3/8 and ANGPTL4/8 were related to concomitant improvements in lipase activity, lipid profile, and cardiometabolic risk factors. These findings reveal the ANGPTL3-4-8 model as a potential molecular mechanism contributing to adaptations in lipid metabolism in response to exercise training., Competing Interests: Conflict of interest Y. Q. C. and R. J. K. are Eli Lilly and Company employees and own Lilly stock. M. A. S. reports that financial support was provided by the National Institutes of Health. G. S. reports that financial support was provided by Eli Lilly and Company. J. S. M. M. reports that financial support was provided by the National Institutes of Health. R. E. G. reports that financial support was provided by the National Institutes of Health. R. J. K. and Y. Q. C. report a relationship with Eli Lilly and Company that includes employment and equity or stocks. All other authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

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., Competing Interests: Declaration of interests M.D.B. reports investigator-initiated grants from Amgen and Boehringer-Ingelheim. P.N. reports investigator-initiated grants from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis and personal fees from Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Novartis, Roche/Genentech; is a co-founder of TenSixteen Bio; is a shareholder of geneXwell, TenSixteen Bio, and Vertex; is a scientific advisory board member of geneXwell and TenSixteen Bio; and reports spousal employment at Vertex, all unrelated to the present work., (Copyright © 2023. Published by Elsevier Inc.)

Regular exercise has many favorable effects on human health, which may be mediated in part by the release of circulating bioactive factors during each bout of exercise. Limited data exist regarding the kinetic responses of plasma proteins during and after acute exercise. Proteomic profiling of 4163 proteins was performed using a large-scale, affinity-based platform in 75 middle-aged adults who were referred for treadmill exercise stress testing. Plasma proteins were quantified at baseline, peak exercise, and 1-h postexercise, and those with significant changes at both exercise timepoints were further examined for their associations with cardiometabolic traits and change with aerobic exercise training in the Health, Risk Factors, Exercise Training and Genetics Family Study, a 20-week exercise intervention study. A total of 765 proteins changed (false discovery rate < 0.05) at peak exercise compared to baseline, and 128 proteins changed (false discovery rate < 0.05) at 1-h postexercise. The 56 proteins that changed at both timepoints included midkine, brain-derived neurotrophic factor, metalloproteinase inhibitor 4, and coiled-coil domain-containing protein 126 and were enriched for secreted proteins. The majority had concordant direction of change at both timepoints. Across all proteins assayed, gene set enrichment analysis showed increased abundance of coagulation-related proteins at 1-h postexercise. Forty-five proteins were associated with at least one measure of adiposity, lipids, glucose homeostasis, or cardiorespiratory fitness in Health, Risk Factors, Exercise Training and Genetics Family Study, and 20 proteins changed with aerobic exercise training. We identified hundreds of novel proteins that change during acute exercise, most of which resolved by 1 h into recovery. Proteins with sustained changes during exercise and recovery may be of particular interest as circulating biomarkers and pathways for further investigation in cardiometabolic diseases. These data will contribute to a biochemical roadmap of acute exercise that will be publicly available for the entire scientific community., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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 ( V̇ O 2 R) 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 V̇ O 2max , were used to calculate the individual linear regressions between %HRR and % V̇ O 2 R. 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 V̇ O 2max as independent variables. The mean %HRR-% V̇ O 2 R 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-% V̇ O 2 R 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-% V̇ O 2 R relationship of a given subject, even when several individual characteristics are considered. Highlights The association between %HRR and % V̇ O 2 R is not 1:1 even when individuals are grouped by age, sex, ethnicity, body composition, HR rest , and V̇ O 2max .Using several subject characteristics to identify the individual's %HRR-% V̇ O 2 R relationship does not meaningfully increase its prediction accuracy or reduce the interindividual variability of %HRR-% V̇ O 2 R relationshipsUsing 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-% V̇ O 2 R relationship should be periodically assessed due to the potential training induced changes in the relationship.

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., Competing Interests: Conflict of interest Y.C., Y-W.Q., and R.K. are Eli Lilly and Company employees and own Lilly stock. C.B. has received meeting travel expenses from the British Physiological Society. G.S. has received research funding from Numares AG, Sanofi, Bayer, and Eli Lilly; consulting fees from Sanofi; honoraria from Sanofi and Daiichi Sankyo; meeting travel expenses from Bayer, Amgen, and Daiichi Sankyo; and research materials from Eli Lilly. H.S. has received research grants and support from Abbott Diagnostics and Amgen and honoraria from Amgen and Sanofi. M.K. has received employment from SYNLAB Holding, Deutschland. M.S. reports NIH funding (R01NR019628, R01HL146462, R01DK128057) and has received consulting fees from Genetic Direction. W.M. has received grants from Siemens, AstraZeneca, Bayer Vital, Bestbion Dx, Boehringer Ingelheim, Immundiagnostik, Merck Chemicals, and Olink; grants and personal fees from Aegerion, Amgen, Sanofi, Amryt Pharma, BASF, Abbott Diagnostics, Numares AG, Berlin-Chemie, Akcea Therapeutics, and Novartis; personal fees from Vifor Pharma; and employment from SYNLAB Holding Deutschland. A.S., M.H., M.R. and T.S. declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© 2023 by the American Diabetes Association.)

Regular exercise leads to widespread salutary effects, and there is increasing recognition that exercise-stimulated circulating proteins can impart health benefits. Despite this, limited data exist regarding the plasma proteomic changes that occur in response to regular exercise. Here, we perform large-scale plasma proteomic profiling in 654 healthy human study participants before and after a supervised, 20-week endurance exercise training intervention. We identify hundreds of circulating proteins that are modulated, many of which are known to be secreted. We highlight proteins involved in angiogenesis, iron homeostasis, and the extracellular matrix, many of which are novel, including training-induced increases in fibroblast activation protein (FAP), a membrane-bound and circulating protein relevant in body-composition homeostasis. We relate protein changes to training-induced maximal oxygen uptake adaptations and validate our top findings in an external exercise cohort. Furthermore, we show that FAP is positively associated with survival in 3 separate, population-based cohorts.

Background: The US Dietary Guidelines (USDG) form the basis of nutrition guidelines, but the research informing the 3 USDG dietary patterns (Healthy US-Style [H-US], Mediterranean [Med], and vegetarian [Veg]) has been drawn largely from observational studies among White populations., Objectives: The Dietary Guidelines 3 Diets study was a 3-arm, 12-wk randomly assigned intervention among African American (AA) adults at risk of type 2 diabetes mellitus that tested the 3 USDG dietary patterns., Methods: The AAs (ages 18-65 y, BMI 25-49.9 kg/m 2 , and BMI was measured in kg/m 2 ) with ≥3 type 2 diabetes mellitus risk factors were recruited. Weight, HbA1c, blood pressure, and dietary quality (healthy eating index [HEI]) were collected at baseline and 12 wk. In addition, participants attended weekly online classes that were designed using material from the USDG/MyPlate. Repeated measures, mixed models with maximum likelihood estimation, and robust computation of standard errors were tested., Results: Of the 227 participants screened, 63 were eligible (83% female; age 48.0 ± 10.6 y, BMI 35.9 ± 0.8 kg/m 2 ) and randomly assigned to the Healthy US-Style Eating Pattern (H-US) (n = 21, 81% completion), healthy Mediterranean-style eating pattern (Med) (n = 22, 86% completion), or healthy vegetarian eating pattern (Veg) (n = 20, 70% completion) groups. Within-group, but not between groups, weight loss was significant (-2.4 ± 0.7 kg H-US, -2.6 ± 0.7 kg Med, -2.4 ± 0.8 kg Veg; P = 0.97 between group). There was also no significant difference between groups for changes in HbA1c (0.03 ± 0.05% H-US, -0.10 ± 0.05% Med, 0.07 ± 0.06% Veg; P = 0.10), systolic BP (-5.5 ± 2.7 mmHg H-US, -3.2 ± 2.5 mmHg Med, -2.4 ± 2.9 mmHg Veg; P = 0.70), diastolic blood pressure (-5.2 ± 1.8 mmHg H-US, -2.0 ± 1.7 mmHg Med, -3.4 ± 1.9 mmHg Veg; P = 0.41), or HEI (7.1 ± 3.2 H-US, 15.2 ± 3.1 Med, 4.6 ± 3.4 Veg; P = 0.06). Post hoc analyses showed that the Med group had significantly greater improvements in HEI compared to the Veg group (difference = -10.6 ± 4.6; 95% CI: -19.7, -1.4; P = 0.02)., Conclusions: The present study demonstrates that all 3 USDG dietary patterns lead to significant weight loss among AA adults. However, none of the outcomes were significantly different between groups. This trial was registered at clinicaltrials.gov as NCT04981847., (Copyright © 2022 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

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/m 2 . 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.

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.

Introduction/purpose: Overweight or obese adults spend more time sedentary and less time performing physical activity (PA) and are at an increased risk for developing impaired glycemic health. Free-living environments may provide insight into glycemic health in addition to clinical assessments. The purpose of this study was to examine the relationship between PA and glycemic health assessed by continuous glucose monitoring (CGM)., Methods: Twenty-eight overweight or obese adults each wore an accelerometer and CGM over the same 7 consecutive days. Average daily time (minutes and metabolic-equivalent minutes (MET-minutes)) and associated energy expenditure performing light (LPA), moderate-to-vigorous (MVPA), total PA, and standard deviation (SD) across days were calculated. Average daily 24-h and waking glycemia, mean glucose concentration, glycemic variability measured as the continuous overlapping net glycemic action, mean amplitude of glycemic excursions, and mean of daily difference were assessed., Results: LPA MET-minutes per day was positively associated with 24-h and waking glycemia time-in-range and negatively associated with 24-h and waking time in hyperglycemia. Total PA time and the SD of MVPA and total PA time were negatively associated with 24-h mean glucose concentration. Individual-level analysis identified that most participants (50%-71%) expressed negative associations between LPA and MVPA time with 24-h mean glucose concentration, mean amplitude of glycemic excursion, and 4-h continuous overlapping net glycemic action., Conclusions: Expectedly, greater total PA time and intensity-specific PA time were associated with lower 24-h and waking mean glucose concentration, greater glycemia time-in-range, and less time in hyperglycemia. The relationship between glucose concentrations and PA time SD was unexpected, whereas most participants expressed hypothesized relationships, which necessitates further exploration.

Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type II A muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention., (© 2022. The Author(s).)

Integrating genetic information with metabolomics has provided new insights into genes affecting human metabolism. However, gene-metabolite integration has been primarily studied in individuals of European Ancestry, limiting the opportunity to leverage genomic diversity for discovery. In addition, these analyses have principally involved known metabolites, with the majority of the profiled peaks left unannotated. Here, we perform a whole genome association study of 2,291 metabolite peaks (known and unknown features) in 2,466 Black individuals from the Jackson Heart Study. We identify 519 locus-metabolite associations for 427 metabolite peaks and validate our findings in two multi-ethnic cohorts. A significant proportion of these associations are in ancestry specific alleles including findings in APOE, TTR and CD36. We leverage tandem mass spectrometry to annotate unknown metabolites, providing new insight into hereditary diseases including transthyretin amyloidosis and sickle cell disease. Our integrative omics approach leverages genomic diversity to provide novel insights into diverse cardiometabolic diseases., (© 2022. The Author(s).)

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.

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., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Sports Medicine.)

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 < 0.0001, η2 = 0.332). The BID from meta-perception revealed that cheerleaders felt that their coaches wanted them to be the smallest ( p < 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.

Background: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants., Methods: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics)., Results: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10 -11 . These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P =3.27×10 -30 ) and MMP-3 (β=-0.60±0.05, P =1.67×10 -32 ), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P =1.34×10 -17 ) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure., Conclusions: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.

The purpose of this study was to examine individual and combined Female Athlete Triad components within collegiate cheerleaders, an at-risk group. Cheerleaders ( n = 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.

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 (VO 2 max)) with VO 2 max, 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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

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 (S i ) in healthy volunteers, we have identified novel candidate genes whose mouse knockouts phenotypes were consistent with a causative effect on S i . An integrative analysis of functional genomic and transcriptomic profiles suggests genetic variants have an aggregate effect on baseline S i and ∆S i , 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 ∆S i further strengthens the relevance of calcium signalling in EET mediated S i response., (© 2021. The Author(s).)

The state of being overweight or obese leads to an increased risk of development of cardiometabolic disease. Increases in glycemic variability have been associated with greater induction of oxidative stress and declined vascular health, which may be exacerbated by higher weight status and improved through exercise. The purpose of this study was to examine the impact of a twelve-week aerobic exercise intervention on continuous glucose monitor (CGM) assessed glucose concentrations and glycemic variability, and biomarkers of vascular health and oxidative stress in overweight or obese adults. Eight adults (Age = 48.9 ± 5.2 years; BMI = 29.4 ± 8.3 kg/m2) completed a twelve-week aerobic exercise intervention. Participants walked three times per week at moderate intensity for ~150 minutes each week. All participants wore a CGM for seven consecutive days at baseline and post-intervention. On the final day of monitoring, a fasting blood sample was collected, and an oral glucose tolerance test (OGTT) was performed. Intra- and inter-day glycemic variability was assessed as the mean amplitude of glycemic excursions, continuous overlapping net glycemic action of one-, two-, and four-hour, and the mean observation of daily differences. Plasma concentrations of nitric oxide (NO) and myeloperoxidase (MPO) were measured, and their ratio was calculated (NO:MPO). No CGM-assessed glucose concentrations or measures of glycemic variability changed from baseline to post-intervention. MPO concentration decreased (24.8 ± 8.2 ng/mL to 16.4 ± 4.6 ng/mL, p < 0.01), the NO:MPO ratio improved (3.5:1 to 6.4:1, p < 0.01) following the twelve-week intervention. Individual level changes in body weight and V̇O 2 peak were found. In conclusion, twelve weeks of aerobic exercise reduced oxidative stress and improved the propensity to vasodilate but did not alter CGM-assessed glucose concentrations or glycemic variability in this group of overweight or obese non-diabetic adults. These findings may be due to individual changes in body weight or V̇O2peak, which necessitates further research to explore their influence on these outcomes of interest.

Glycemic variability is a more sensitive assessment of glycemic health as opposed to traditional clinical measurements. It considers all blood glucose concentrations over a given period to better account for glucose oscillations that occur and provides clinicians with insight into how individuals regulate and/or maintain their glycemic health. The advancement of continuous glucose monitoring (CGM) allows for the measurement of free-living glucose concentrations while providing a more reliable assessment of treatment of dysregulated glycemic. CGM coupled with management of lifestyle behavioral factors, such as reduced sedentary behavior and increased physical activity and regular exercise, potentially offers a previously untapped method for promoting improved glycemic health through greater regulation of glucose concentrations. The aim of this review is to critically evaluate the evidence regarding the measurement of glycemic variability and summarize the current understanding of the relationship between glycemic variability, sedentary behavior, physical activity, the influence of a single exercise session or repeated exercise sessions, and exercise training. This review considers information pertaining to the strengths and limitations for measuring glycemic variability and provides insight into future study designs aimed at evaluating the relationship between sedentary behavior and physical activity with, as well as the influence of exercise on, glycemic variability as a primary outcome., (© 2021 Chengdu Sport University. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd.)

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.

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 Apc Min /+ (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 AMPKα 1 α 2 (KO) knockout mice crossed with Apc Min /+ 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 AMPK T172 , FOXO S413 , and ULK-1 S555 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., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Maximal oxygen uptake (VO 2 max) is a direct measure of human cardiorespiratory fitness and is associated with health. However, the molecular determinants of interindividual differences in baseline (intrinsic) VO 2 max, and of increases of VO 2 max in response to exercise training (ΔVO 2 max), are largely unknown. Here, we measure ~5,000 plasma proteins using an affinity-based platform in over 650 sedentary adults before and after a 20-week endurance-exercise intervention and identify 147 proteins and 102 proteins whose plasma levels are associated with baseline VO 2 max and ΔVO 2 max, respectively. Addition of a protein biomarker score derived from these proteins to a score based on clinical traits improves the prediction of an individual's ΔVO 2 max. We validate findings in a separate exercise cohort, further link 21 proteins to incident all-cause mortality in a community-based cohort and reproduce the specificity of ~75% of our key findings using antibody-based assays. Taken together, our data shed light on biological pathways relevant to cardiorespiratory fitness and highlight the potential additive value of protein biomarkers in identifying exercise responsiveness in humans.

Introduction: According to current guidelines, the intensity of health-enhancing aerobic exercise should be prescribed using a percentage of heart rate reserve (%HRR), which is considered to be more closely associated (showing a 1:1 relation) with the percentage of oxygen uptake reserve (%V˙O2R) rather than with the percentage of maximal oxygen uptake (%V˙O2max) during incremental exercise. However, the associations between %HRR and %V˙O2R and between %HRR and %V˙O2max are under debate; hence, their actual relationships were investigated in this study., Methods: Data from each stage of a maximal incremental exercise test performed by 737 healthy and physically inactive participants of the HERITAGE Family Study were screened and filtered then used to calculate the individual linear regressions between %HRR and either %V˙O2R or %V˙O2max. For each relationship, the mean slope and intercept of the individual linear regression were compared with 1 and 0 (i.e., the identity line), respectively, using one-sample t-tests. The individual root mean square errors of the actual versus the 1:1 predicted %HRR were calculated for both relationships and compared using a paired-sample t-test., Results: The mean slopes (%HRR-%V˙O2R, 0.972 ± 0.189; %HRR-%V˙O2max, 1.096 ± 0.216) and intercepts (%HRR-%V˙O2R, 8.855 ± 16.022; %HRR-%V˙O2max, -3.616 ± 18.993) of both relationships were significantly different from 1 and 0, respectively, with high interindividual variability. The average root mean square errors were high and revealed that the %HRR-%V˙O2max relationship was more similar to the identity line (P < 0.001) than the %HRR-%V˙O2R relationship (7.78% ± 4.49% vs 9.25% ± 5.54%)., Conclusions: Because both relationships are different from the identity line and using a single equation may not be appropriate to predict exercise intensity at the individual level, a rethinking of the relationships between the intensity variables may be necessary to ensure that the most suitable health-enhancing aerobic exercise intensity is prescribed.

Purpose: We designed the study to determine whether mitochondrial DNA (mtDNA) haplogroup, sequence, and heteroplasmy differed between individuals previously characterized as low (LR) or high responders (HR) as defined by their maximal oxygen uptake response to a standardized aerobic exercise training program., Methods: DNA was isolated from whole blood in subjects from the HERITAGE Family Study that were determined to be either HR (n = 15) or LR (n = 15). mtDNA was amplified by long-range polymerase chain reaction, then tagged with Nextera libraries and sequenced on a MiSeq instrument., Results: Different mtDNA haplogroup subtypes were found in HR and LR individuals. Compared with HR subjects, significantly more LR subjects had variants in 13 sites, including 7 in hypervariable (HV) regions: HV2 (G185A: 0 vs 6, P = 0.02; G228A: 0 vs 5, P = 0.04; C295T: 0 vs 6; P = 0.04), HV3 (C462T: 0 vs 5, P = 0.04; T489C: 0 vs 5; P = 0.04), and HV1 (C16068T: 0 vs 6, P = 0.02; T16125C: 0 vs 6, P = 0.02). Remaining variants were in protein coding genes, mtND1 (1 vs 8, P = 0.02), mtND3 (A10397G: 0 vs 5, P = 0.04), mtND4 (A11250G: 1 vs 8, P = 0.02), mtND5 (G13707A: 0 vs 5, P = 0.04), and mtCYTB (T14797C: 0 vs 5, P = 0.04; C15451A: 1 vs 8, P = 0.02). Average total numbers of heteroplasmies (P = 0.83) and frequency of heteroplasmies (P = 0.05) were similar between the groups., Conclusions: Our findings provide specific sites across the mitochondrial genome that may be related to maximal oxygen uptake trainability.

Importance: Obesity is a major determinant of disease burden worldwide. Polygenic risk scores (PRSs) have been posited as key predictors of obesity. How a PRS can be translated to the clinical encounter (especially in the context of fitness, activity, and parental history of overweight) remains unclear., Objective: To quantify the relative importance of a PRS, fitness, activity, parental history of overweight, and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) in young adulthood on BMI trends over 25 years., Design, Setting, and Participants: This population-based prospective cohort study at 4 US centers included white individuals and black individuals with assessments of polygenic risk of obesity, fitness, activity, and BMI in young adulthood (in their 20s) and up to 25 years of follow-up. Data collected between March 1985 and August 2011 were analyzed from April 25, 2019, to September 29, 2019., Main Outcomes and Measures: Body mass index at the initial visit and 25 years later., Results: This study evaluated an obesity PRS from a recently reported study of 1608 white individuals (848 women [52.7%]) and 909 black individuals (548 women [60.3%]) across the United States. At baseline (year 0), mean (SD) overall BMI was 24.2 (4.5), which increased to 29.6 (6.9) at year 25. Among white individuals, the PRS (combined with age, sex, self-reported parental history of overweight, and principal components of ancestry) explained 11.9% (at year 0) and 13.6% (at year 25) of variation in BMI. Although the addition of fitness increased the explanatory capability of the model (24.0% variance at baseline and up to 18.1% variance in BMI at year 25), baseline BMI in young adulthood was the strongest factor, explaining 52.3% of BMI in midlife in combination with age, sex, and self-reported parental history of overweight. Accordingly, models that included baseline BMI (especially BMI surveillance over time) were better in predicting BMI at year 25 compared with the PRS. In fully adjusted models, the effect sizes for fitness and the PRS on BMI were comparable in opposing directions. The added explanatory capacity of the PRS among black individuals was lower than among white individuals. Among white individuals, addition of baseline BMI and surveillance of BMI over time was associated with improved precision of predicted BMI at year 25 (mean error in predicted BMI 0 kg/m2 [95% CI, -11.4 to 11.4] to 0 kg/m2 [95% CI, -8.5 to 8.5] for baseline BMI and mean error 0 kg/m2 [95% CI, -5.3 to 5.3] for BMI surveillance)., Conclusions and Relevance: Cardiorespiratory fitness in young adulthood and a PRS are modestly associated with midlife BMI, although future BMI is associated with BMI in young adulthood. Fitness has a comparable association with future BMI as does the PRS. Caution should be exercised in the widespread use of polygenic risk for obesity prevention in adults, and close clinical surveillance and fitness may have prime roles in limiting the adverse consequences of elevated BMI on health.