Exercise training induces adaptations to the body that improve metabolic health; however, the molecular mechanisms mediating these beneficial adaptations to training are not well characterized. We hypothesized that exercise training causes adaptations to multiple tissues (e.g., muscle, adipose) that lead to altered secretion of factors from these tissues into the circulation, and that these circulating factors may contribute to the effects of exercise training on metabolic health. To identify novel exercise training-stimulated circulating factors, healthy subjects (n=8, 3 males and 5 females; age=27.0 ± 2.2 years; BMI=21.9 ± 0.9 kg/m2; V?O2peak=28.4 ± 1.2 ml/kg/minute) underwent 10-weeks of aerobic exercise training. Training increased V?O2peak by 17% (p=<0.003). Fasting blood samples were collected pre- and post-training, and 1,310 circulating factors were measured in plasma using aptamer-based proteomics. Remarkably, exercise training significantly altered 293 (22%) of all circulating factors. 164 proteins were increased and 129 proteins were decreased; the majority of which have not been previously identified as exercise training-induced factors. Change in V?O2peak most significantly correlated with baseline levels of Mesothelin (p<0.001, R=0.53), a cell-surface protein that may regulate Insulin-like Growth Factor transport. Change in V?O2peak was also highly correlated with Protein Kinase C Zeta (p=0.005, R=0.3), a kinase involved in AKT3-PI3K signaling and adipocyte glucose transport. Pathway analysis revealed downregulation of the lysosomal pathway, and upregulation of pathways including FC Epsilon Ri signaling, Mtor signaling and WNT signaling, suggesting that exercise training adaptations involve multiple processes, including cellular growth, proliferation and protein degradation. These data define proteomic adaptations to exercise training, and identify biological processes that may mediate the beneficial effects of exercise training in humans.


R. Middelbeek: None. J.J. Richard: None. L.A. Rowland: None. P. Nigro: None. H. Pan: None. J. Dreyfuss: None. L.J. Goodyear: None.


National Institutes of Health (R01DK099511 to L.J.G.), (K23DK114550 to R.M.); Joslin Diabetes Center (5P30DK36836); Daiichi Sankyo (to L.J.G.); Boston Area Diabetes Endocrinology Research Center (to R.M.)

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