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

• 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
• 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

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).

项目概要/摘要 定期锻炼可以改善许多代谢和心血管健康特征，并预防或延迟 尽管运动对健康有多种作用，但也有一些影响。 对定期运动的心脏代谢反应存在显着的个体差异，甚至是严格的运动 标准化锻炼计划的能力。 基因组下游使得血浆代谢组学和蛋白质组学非常适合研究运动- 最近，我们的团队利用了非靶向代谢分析。 鉴定二甲基胍戊酸 (DMGV) 作为心脏代谢的新型早期生物标志物的方法 DMGV 存在于丙氨酸-乙醛酸转氨酶 2 催化的生化途径中。 (AGXT2) 具有多种生物活性底物和产品，可通过运动刺激、调节 运动代谢或影响心血管生理学这些发现激发了我们最近的研究。 DMGV 作为运动训练 (ET) 代谢反应性的生物标志物，我们在其中证明了 DMGV 基线水平较高的个体对脂质特征和胰岛素的改善反应较弱 然而，与该新型相关的其他代谢物和蛋白质的数据很少。 运动反应性背景下的途径。 健康、风险因素、运动训练和遗传学 (HERITAGE) 家庭研究提供了极好的 用于全面研究 DMGV 和心脏代谢的其他分子相关性的资源 我们勇敢地说，生物活性 AGXT2 通路成员将与有氧 ET 相关。 运动特征反应性（即最大摄氧量、胰岛素敏感性、内脏脂肪和高密度脂蛋白胆固醇） 我们进一步追求整合大规模代谢组学和 具有这些关键表型的蛋白质组学将识别其他血浆生物标志物，帮助确定哪些 个人从定期锻炼中受益最多。 在具体目标 1 中，我们将 AGXT2 通路参与者与 ET 诱导的 VO2max、胰岛素结果联系起来 然后，我们将把我们的调查范围扩大到约 800 个样本。 已知的代谢物/脂质和约 5000 种蛋白质，以创建全面的血浆生化/分子 我们将验证四种临床特征中每一种的运动反应性特征。 NIH 的体力活动分子传感器 (MoTrPAC) 研究对 800 多名健康成年人进行了研究 ET 计划中，我们将确定“运动反应”的遗传决定因素。 然后将在以下方面对这些代谢物和蛋白质进行询问：1) HERITAGE 以测试它们的情况。 与运动特质反应的关系；2) 大型遗传学荟萃分析 心脏代谢特征和长期结果（孟德尔随机化）。