Specific circulating microRNAs display dose-dependent responses to variable intensity and duration of endurance exercise

Circulating microRNAs (c-miRNAs) - plasma-based noncoding RNAs that control post-transcriptional gene expression - mediate processes that underlie phenotypic plasticity to exercise. The relationship and biologic relevance between c-miRNA expression and variable dose exercise exposure remain uncertain. We hypothesized that certain c-miRNAs respond to changes in exercise intensity and/or duration in a dose-dependent fashion. Muscle release of such c-miRNAs may then deplete intracellular stores, thus facilitating gene reprogramming and exercise adaptation. To address these hypotheses, healthy men participated in variable intensity (n=12, 30 min x 1 at 6, 7, and 8 m.p.h., order randomized) and variable duration (n=14, 7 m.p.h. x 1 for 30, 60, and 90 min., order randomized) treadmill running protocols. Muscle-enriched c-miRNAs (i.e., miRs-1, 133a) and others with known relevance to exercise were measured before and after exercise. C-miRNA responses followed three profiles: (1) non-responsive (miRs-21, 210); (2) responsive to exercise at some threshold but without dose-dependence (miRs-24, 146a); and (3) responsive to exercise with dose-dependence to increasing intensity (miR-1) or duration (miR-133a, 222). We also studied aerobic exercise-trained mice, comparing control, low intensity (0.5 km/hr), or high intensity (1 km/hr) treadmill running protocols over 4 weeks. In high, but not low, intensity trained mice, we found increased plasma c-miR-133a along with decreased intracellular miR-133a and increased SRF, a known miR-133a target gene, in muscle. Characterization of c-miRNAs that are dose-responsive to exercise in humans and mice supports the notion that they directly mediate physiologic adaptation to exercise, potentially through depletion of intracellular stores of muscle-specific miRNAs.