Biochemical profiling to identify cardiometabolic responsiveness to an endurance exercise intervention

项目概要/摘要 经常锻炼可以改善许多代谢和心血管健康特征，预防或延迟心脏病。 心脏代谢疾病的发展。尽管运动对健康有多种影响， 有规律的运动，即使是严格的运动， 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研究运动， 诱导心脏代谢适应。最近，我们的团队利用非靶向代谢物分析 一种鉴定二甲基胍基戊酸（DMGV）作为心脏代谢的新的早期生物标志物的方法， 疾病DMGV存在于由丙氨酸乙醛酸转氨酶2催化的生化途径中 （AGXT 2）具有多种生物活性底物和产物，这些底物和产物由运动刺激，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的调查， DMGV作为运动训练（ET）代谢反应性的生物标志物，我们证明， DMGV基线水平较高的个体对脂质性状和胰岛素改善的反应较低 对ET的敏感性然而，很少有数据可用于其他代谢物和蛋白质相关的这一新的 在运动反应的背景下。 健康，风险因素，运动训练和遗传学（遗产）家庭研究提供了一个很好的 DMGV和其他心脏代谢相关分子的综合研究资源 对有氧ET的反应。我们假设生物活性AGXT 2通路成员将与 运动特质反应性（即VO 2 max、胰岛素敏感性、内脏脂肪和HDL-胆固醇）， 合理的生物学关系。我们进一步假设，整合大规模代谢组学和 这些关键表型的蛋白质组学将确定其他血浆生物标志物， 个人最受益于定期锻炼。 在具体目标1中，我们将AGXT 2通路参与者与ET诱导的VO 2 max、胰岛素 敏感性、内脏脂肪和HDL-胆固醇。然后，我们将扩大我们的调查，以一个完整的小组约800 已知的代谢物/脂质和约5000种蛋白质，以产生全面的血浆生化/分子 四个临床特征中的每一个的运动反应性的签名。我们将验证 NIH的身体活动分子传感器（MoTrPAC）研究，800多名健康成年人被分配到一个 耐力计划在具体目标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。然后将在以下方面对这些遗传基因座进行询问：1）遗传以测试其 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局（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).