Biochemical profiling to identify cardiometabolic responsiveness to an endurance exercise intervention

通过生化分析来确定心脏代谢对耐力运动干预的反应

基本信息

批准号：
10363615
负责人：
ROBERT E GERSZTEN
金额：
$ 57.44万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-03 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10363615
关键词：
Adult Aerobic Exercise Affect African American Age Alanine-glyoxylate aminotransferase Biochemical Biochemical Pathway Biological Biological Markers Cardiometabolic Disease Cardiovascular Physiology Cardiovascular system Clinical Data Data Set Development Diabetes Mellitus Disease Enzymes Exercise Family Study Fatty acid glycerol esters Female Future Genetic Genetic Determinism Genome Genomics Goals Guidelines Health Heart Diseases High Density Lipoprotein Cholesterol Individual Individual Differences Investigation Jackson Heart Study Lipids Liver Mendelian randomization Meta-Analysis Metabolic Metabolic Diseases Metabolism Methods Molecular Molecular Profiling Outcome Participant Pathway interactions Phenotype Physical activity Plasma Population Prevention Primary Prevention Proteins Proteomics Protocols documentation Resources Risk Factors Standardization Supervision Testing Training Programs Transducers United States National Institutes of Health VO2max Visceral fat base cardiometabolism cardiovascular disorder prevention cardiovascular health caucasian American clinical biomarkers cohort early detection biomarkers effective intervention endurance exercise exercise intensity exercise intervention exercise program exercise regimen exercise training family genetics genomic locus improved insight insulin sensitivity interest member metabolic phenotype metabolomics n-pentanoic acid novel population based prevent protein metabolite response sedentary sex trait

项目摘要

Project Summary/Abstract Regular exercise improves numerous metabolic and cardiovascular health traits and prevents or delays the development of cardiometabolic disease. Despite the pleiotropic health effects of exercise, there are substantial inter-individual differences in the cardiometabolic responses to regular exercise, even to rigorously standardized exercise programs. The ability to systematically interrogate metabolites and proteins that are downstream of the genome makes plasma metabolomics and proteomics well-suited for investigating exercise- induced cardiometabolic adaptations. Recently, our group leveraged a non-targeted metabolite profiling method to identify dimethylguanidino valeric acid (DMGV) as a novel, early biomarker of cardiometabolic disease. DMGV lies in a biochemical pathway catalyzed by the enzyme alanine-glyoxylate aminotransferase 2 (AGXT2) that features multiple bioactive substrates and products that are stimulated by exercise, regulate exercise metabolism, or affect cardiovascular physiology. These findings motivated our recent investigation of DMGV as a biomarker of metabolic responsiveness to exercise training (ET), in which we demonstrated that individuals with higher baseline levels of DMGV are less responsive to improvements in lipid traits and insulin sensitivity with ET. However, few data are available for other metabolites and proteins related to this novel pathway in the context of exercise responsiveness. The HEalth, RIsk factors, exercise Training And GEnetics (HERITAGE) Family Study provides an excellent resource for a comprehensive study of DMGV and additional molecular correlates of the cardiometabolic responses to aerobic ET. We hypothesize that bioactive AGXT2 pathway members will be associated with exercise trait responsiveness (i.e. VO2max, insulin sensitivity, visceral fat, and HDL-cholesterol) based on plausible biologic relationships. We further hypothesize that integrating large-scale metabolomics and proteomics with these key phenotypes will identify additional plasma biomarkers that help determine which individuals benefit most from regular exercise. In Specific Aim 1, we will relate AGXT2 pathway participants to ET-induced outcomes of VO2max, insulin sensitivity, visceral fat, and HDL-cholesterol. We will then extend our investigations to a full panel of ~800 known metabolites/lipids and ~5000 proteins to create comprehensive plasma biochemical/molecular signatures of exercise responsiveness for each of the four clinical traits. We will validate top findings in the NIH's Molecular Transducers of Physical Activity (MoTrPAC) Study of over 800 healthy adults assigned to an endurance ET program. In Specific Aim 2, we will identify the genetic determinants of “exercise response” metabolites and proteins. These genetic loci will then be interrogated in: 1) HERITAGE to test for their relationship with exercise trait responses; and 2) large genetics meta-analyses for associations with cardiometabolic traits and long-term outcomes (Mendelian Randomization).

项目摘要/摘要定期锻炼可改善许多代谢和心血管健康特征，并防止或延迟心脏代谢疾病的发展。尽管锻炼的多效性健康影响，但仍有心脏代谢反应对定期运动的较大个体间差异，甚至严格标准化锻炼计划。系统询问代谢物和蛋白质的能力基因组下游使血浆代谢组学和蛋白质组学非常适合研究运动诱导心脏代谢适应。最近，我们的小组利用了非目标的代谢物分析识别二甲基圭尼诺阀酸（DMGV）的方法是一种新颖的，早期的心脏代谢生物标志物疾病。 DMGV位于由酶丙氨酸 - 甘酰胺氨基转移酶2催化的生化途径（AGXT2）具有多种生物活性底物和锻炼刺激的产品，调节运动代谢或影响心血管生理。这些发现激发了我们最近对 DMGV是对运动训练的代谢反应性（ET）的生物标志物（ET），我们证明 DMGV基线水平较高的个体对脂质性状和胰岛素的改善的反应较低对ET的敏感性。但是，几乎没有数据可用于与这一新小说有关的其他代谢物和蛋白质在锻炼响应能力的背景下的途径。健康，危险因素，运动训练和遗传学（遗产）家庭研究提供了出色的用于全面研究DMGV和心脏代谢的其他分子相关的资源对有氧运动的反应。我们假设生物活性AGXT2途径成员将与基于运动特征的反应能力（即vo2max，胰岛素敏感性，内脏脂肪和HDL-胆固醇）合理的生物关系。我们进一步假设将大规模代谢组学和具有这些关键表型的蛋白质组学将确定其他等离子体生物标志物，以帮助确定哪个个人从定期运动中受益最大。在特定目标1中，我们将将Agxt2途径参与者与ET诱导的VO2MAX，胰岛素的结果联系起来敏感性，内脏脂肪和HDL-胆固醇。然后，我们将调查扩展到〜800的完整面板已知的代谢产物/脂质和〜5000蛋白，以创建全面的等离子体生化/分子四个临床特征中每个特征的运动反应性的签名。我们将在 NIH的体育活动分子换能器（MOTRPAC）研究了800多名健康成年人 Endurance ET程序。在特定的目标2中，我们将确定“运动反应”的遗传决定者代谢物和蛋白质。然后，这些遗传基因座将在：1）测试其测试的遗产中进行审问与运动特征反应的关系； 2）与与心脏代谢性状和长期结局（门德利随机化）。