Abstract 15255: Statins Augment Circulating MicroRNA-499-5p Release With Muscle Contraction and Aerobic Exercise

Abstract

Background: Statins exacerbate exercise-induced skeletal muscle injury. Muscle-specific microRNAs (myomiRs) increase in plasma after prolonged exercise, but the patterns of myomiRs release after statin-associated muscle injury have not been examined. Objectives: We examined the relationships among statin exposure, in vitro and in vivo muscle contraction, and candidate circulating myomiRs expression. Methods: We measured plasma levels of the myomiRs, circulating microRNA-1 (c-miR-1), c-miR-133a, c-miR-206 and c-miR-499-5p, from 28 statin-using and 28 non-statin using runners before (PRE), immediately after (FINISH), and 24 hours after a 42 km footrace (POST-24). We subsequently used contracting mouse C2C12 cultured myotubes with and without statin exposure to compare intracellular and extracellular expression of these molecules. Fold-changes of microRNAs are presented as median [interquartile range]. Results: In marathoners, c-miR-1, c-miR-133a, and c-miR-206 increased at FINISH, returned to baseline at POST-24, and were unaffected by statin use. In contrast, c-miR-499-5p was unchanged at FINISH in both groups, but c-miR-499-5p increased in statin users at the POST-24 time point compared to PRE [2.9 (1.3, 8.6) vs. 1.0 fold change, p <0.001] and to non-statin using runners [2.9 (1.3, 8.6) vs. 1.4 (0.9, 3.2) fold change, p < 0.05]. In cultured C2C12 myotubes, intracellular levels of candidate myomiRs remained stable except for modest declines of miR-1 and miR-206 with isolated myotube contraction (carbachol exposure) or simultaneous statin and myotube contraction. Extracellular miR-1, 133a, and 206 increased with contraction regardless of statin use. In contrast, extracellular miR-499-5p was unaffected by either isolated statin exposure or isolated contraction but increased with contraction + statin [4.8 (1.9, 8.1) vs. 1.0 (0.7, 1.5) fold change, p < 0.05 vs. control]. Conclusions: Statin-potentiated muscle injury during exercise is accompanied by augmented extracellular release of miR-499-5p. c-miR-499-5p may serve as a biomarker of statin-potentiated muscle damage.