Distance running alters peripheral microRNAs implicated in metabolism, fluid balance, and myosin regulation in a sex-specific manner

Abstract

Microribonucleic acids (miRNAs) mediate adaptive responses to exercise and may serve as biomarkers of exercise intensity/capacity. Expression of miRNAs is altered in skeletal muscle, plasma, and saliva following exertion. Women display unique physiologic responses to endurance exercise, and miRNAs respond to pathologic states in sex-specific patterns. However sex-specific miRNA responses to exercise remain unexplored. This study utilized high-throughput RNA sequencing to measure changes in salivary RNA expression among 25 collegiate runners following a single long-distance run. RNA concentrations in pre-and post-run saliva was assessed through alignment and quantification of 4,694 miRNAs and 27,687 mRNAs. Pair-wise Wilcoxon rank-sum test identified miRNAs with significant [false discovery rate (FDR) < 0.05] post-run changes. Associations between miRNA levels and predicted mRNA targets were explored with Pearson correlations. Differences in miRNA patterns between men (n = 13) and women (n = 12) were investigated with two-way analysis of variance. Results revealed 122 salivary miRNAs with post-run changes. The eight miRNAs with the largest changes were miR-3671, miR-5095 (downregulated); and miR-7154-3p, miR-200b-5p, miR-5582-3p, miR-6859-3p, miR-6751-5p, miR-4419a (upregu-lated). Predicted mRNA targets for these miRNAs represented 15 physiologic processes, including glycerophospholipid metabolism (FDR = 0.042), aldosterone-regulated sodium reabsorption (FDR = 0.049), and arrhythmogenic ventricular cardiomyopathy (FDR = 0.018). Twenty-six miRNA/mRNA pairs had associated changes in post-run levels. Three miRNAs (miR-4675, miR-6745, miR-6746-3p) demonstrated sex-specific responses to exercise. Numerous salivary miRNAs change in response to endurance running and target the expression of genes involved in metabolism, fluid balance, and mus-culoskeletal adaptations. A subset of miRNAs may differentiate the metabolic response to exercise in men and women.