Biochemical profiling to identify cardiometabolic responsiveness to an endurance exercise intervention

项目摘要/摘要 有规律的锻炼可以改善新陈代谢和心血管健康状况，预防或延缓 心脏代谢性疾病的发展。尽管运动对健康有多方面的影响，但还有 有规律的运动，即使是剧烈的运动，心脏代谢反应的个体间差异很大 标准化的锻炼计划。系统地询问代谢物和蛋白质的能力 基因组的下游使得血浆代谢组学和蛋白质组学非常适合于研究运动- 诱导心脏新陈代谢适应。最近，我们的团队利用了一种非靶向代谢物分析 一种新的心脏代谢早期生物标志物--二甲基胍基戊酸的鉴定方法 疾病。DMGV是由丙氨酸乙醛转氨酶2催化的生化途径 (AGXT2)，以运动刺激的多种生物活性底物和产品为特色，调节 运动代谢，或影响心血管生理。这些发现促使我们最近对 DMGV作为运动训练(ET)代谢反应的生物标志物，我们在其中证明了 DMGV基线水平较高的个体对血脂和胰岛素改善的反应较差 对ET的敏感性。然而，与这一新发现相关的其他代谢物和蛋白质的数据很少。 在运动反应的背景下的路径。 健康、危险因素、运动训练和遗传(遗传)家庭研究提供了一个极好的 全面研究DMGV和心脏代谢的其他分子相关性的资源 对需氧ET的反应。我们假设具有生物活性的AGXT2通路成员将与 运动特质反应性(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) 看似合理的生物关系。我们进一步假设，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有助于确定哪些血浆生物标志物 个人从定期锻炼中受益最大。 在特定的目标1中，我们将AGXT2通路的参与者与ET诱导的VO2max、胰岛素的结果联系起来 敏感度、内脏脂肪和高密度脂蛋白胆固醇。然后我们将把我们的调查扩大到一个由大约800人组成的小组 已知的代谢物/脂类和~5000种蛋白质，创造全面的血浆生化/分子 四种临床特征中每一种的运动反应特征。我们将验证最新调查结果 美国国立卫生研究院对800多名健康成年人进行的体力活动分子传感器(MoTrPAC)研究 耐力等项目。在具体目标2中，我们将确定“运动反应”的遗传决定因素。 代谢物和蛋白质。这些遗传基因座随后将在：1)遗传中进行询问，以测试它们的 与运动特质反应的关系；以及2)对与运动特质反应相关的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)。

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).