Exercise Regulates the Concentration of Novel Circulating Factors in Humans

Exercise can improve metabolic health for all people and patients with diabetes; however, the molecular mechanisms that mediate the exercise response are not well understood. We and others have hypothesized that exercise causes factors to be released from skeletal muscles, adipose tissue, and possibly other tissues into the circulation, and that these factors may contribute to the beneficial effects of exercise on health. To identify novel exercise-stimulated factors, healthy subjects (n=6 males and 6 females; age=29.2±0.6 years; BMI=22.5±0.7; VO₂peak=40.6±1.3ml/kg/min) performed 45min of treadmill exercise at 75% VO₂peak. Blood was collected at baseline, 15min, 45min during acute exercise, and 1 hour post-exercise and 1,310 circulating factors were measured using an aptamer-based proteomic method. Remarkably, this single bout of moderate intensity exercise significantly altered 247 or 19% of the measured circulating factors. In total, 171 unique proteins were increased and 76 proteins were decreased. Importantly, based on our literature review, ∼85% of these proteins have not been previously identified as exercise-stimulated circulating factors. Cardiorespiratory fitness (VO₂peak) significantly correlated with the concentration of 112 factors at rest, suggesting that some of these proteins may be biomarkers of cardiorespiratory fitness. Of these factors, baseline concentrations of 40S ribosomal protein S3, a multi-functional protein that has been reported to be present in exosomes, correlated most strongly with VO₂peak (p<0.0007). This data set will provide the basis for ongoing studies to unravel the mechanisms by which exercise mediates its beneficial effects on diabetes and overall health.

In summary, we have identified >200 novel exercise-stimulated proteins and >100 circulating proteins that correlate with cardiorespiratory fitness level in healthy human subjects.