Document text
Principal Investigator: ROBERT E GERSZTEN
Organization: BETH ISRAEL DEACONESS MEDICAL CENTER
Fiscal Year: 2024
Award: $512,548
Funding agency: National Institute of Nursing Research
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).
Terms: <21+ years old><Adult><Adult Human><Aerobic Activity><Aerobic Exercise><Aerobic Training><Aerobic fitness><Affect><African American><Afro American><Afroamerican><Age><Alanine-glyoxylate aminotransferase><Biochemical><Biochemical Pathway><Biological><Biological Markers><Blood Plasma><CVD prevention><Cardiac Diseases><Cardiac Disorders><Cardiometabolic Disease><Cardiometabolic Disorder><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular Physiology><Cardiovascular system><Clinical><Data><Data Set><Development><Diabetes Mellitus><Disease><Disorder><Enzyme Gene><Enzymes><Exercise><Exercise routine><Family Study><Fats><Fatty acid glycerol esters><Female><Future><Genetic><Genetic Determinism><Genome><Goals><Guidelines><HDL Cholesterol><HDL Cholesterol Lipoproteins><Health><Heart Diseases><Heart Vascular><High Density Lipoprotein Cholesterol><Individual><Individual Differences><Intermediary Metabolism><Investigation><Jackson Heart Study><Lipids><Liver><Mendelian randomization><Meta-Analysis><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Networks><Metabolic Processes><Metabolism><Methods><Molecular><Molecular Fingerprinting><Molecular Profiling><NIH><National Institutes of Health><Outcome><Participant><Pathway interactions><Phenotype><Physical activity><Plasma><Plasma Serum><Population><Prevention><Primary Prevention><Proteins><Proteomics><Protocol><Protocols documentation><Research Resources><Resources><Reticuloendothelial System, Serum, Plasma><Risk Factors><Standardization><Testing><Thesaurismosis><Training Programs><Transducers><United States National Institutes of Health><VO2 max><VO2max><Visceral fat><adulthood><ages><alpha-Lipoprotein Cholesterol><bio-markers><biologic><biologic marker><biomarker><cardiac disease prevention><cardiometabolic><cardiometabolism><cardiovascular disease prevention><cardiovascular disorder prevention><cardiovascular function><cardiovascular health><caucasian American><circulatory system><clinical biomarkers><clinically useful biomarkers><cohort><developmental><diabetes><early biomarkers><early detection biomarkers><early detection markers><effective intervention><endurance exercise><exercise intensity><exercise intervention><exercise program><exercise regimen><exercise training><family genetics><fitness program><gene locus><genetic determinant><genetic locus><genome resource><genomic data resource><genomic location><genomic locus><genomic resource><genomic sequencing resource><heart disorder><hepatic body system><hepatic organ system><improved><insight><insulin sensitivity><interest><maximal oxygen uptake><member><metabolic phenotype><metabolism disorder><metabolism measurement><metabolomics><metabonomics><metabotype><molecular profile><molecular signature><n-pentanoic acid><novel><pathway><physical activity intervention><population based><prevent><preventing><response><sedentary><sex><trait><valeric acid><white American>