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).

Project Narrative Exercise is an effective intervention for both the prevention and treatment of heart and metabolic diseases, though there are substantial differences in how any given individual responds. Our goal is to better understand the fundamental mechanisms by which exercise confers its beneficial effects and in doing so determine which individuals benefit most from regular exercise.