Abstract 14285: Plasma Proteomic Profiling of Endurance Exercise Identifies Changes in Extracellular Matrix Biology Associated With Adaptations in Maximal Oxygen Uptake

Introduction: Proteins are important regulators of cardiometabolic health that are increasingly recognized as being modulated by exercise. Hypothesis: We measured approximately 5,000 plasma proteins before and after an endurance exercise training (ET) program to test the hypothesis that proteomic changes are related to adaptations in maximal oxygen uptake ( Δ VO2max) and long-term health outcomes. Methods: We applied an affinity-based proteomics platform before and after ET in 654 sedentary participants (mean age = 35, 35% black) from the HERITAGE Study. Subjects performed graded cycle ergometry, exercising at 75% VO2max, 3x/week over the final 6 weeks of a 20-week program. Changes in plasma protein levels after ET were determined using paired t tests. Multivariate linear regression assessed the relationship between Δ protein and Δ VO2max after ET. Statistical significance was determined using a false discovery rate (FDR) < 0.05. Multivariate cox proportional hazards regression estimated hazard ratios (HR) of protein levels and all-cause mortality in the Framingham Heart Study (FHS) and Malmo Diet and Cancer Study (MDCS). Results: 455 proteins changed after ET, including 306 proteins that increased. Proteins related to the extracellular matrix (ECM) were overrepresented among biologic processes and pathways in enrichment analyses. Absolute changes in five proteins after ET were related to ΔVO2max [FTH1: (β = -31.8, q = 0.009), CDH5 (β = 28.3, q = 0.028), FAP (β = 28.0, q = 0.025), ANGPT2 (β = 28.1, q = 0.028), PRELP (β = 26.6, q = 0.044) after adjustment for age, sex, race, BMI, and baseline VO2max. Fibroblast activation protein (FAP), was positively associated with baseline VO2max (β = 43.6, p = 0.02) and inversely related to all-cause mortality in FHS and MDCS (HR = 0.84 and 0.86, p = 0.0002 and 0.004, respectively). Conclusions: Endurance exercise leads to large-scale plasma proteomic changes, including increased levels of ECM-related proteins. Several novel proteins modulated by ET were associated with Δ VO2max, including FAP, a serine protease relevant in wound healing and metabolism that is inversely associated with mortality in two separate cohorts. External validation and additional efforts to understand FAP’s mechanistic relevance are warranted.