Min Pil-Ki, Park Joseph, Isaacs Stephanie, Taylor Beth A, Thompson Paul D, Troyanos Chris, D'Hemecourt Pierre, Dyer Sophia, Chan Stephen Y, Baggish Aaron L
Brigham and Women's Hospital, Division of Cardiovascular Medicine, Department of Medicine, Harvard Medical School, Boston, Massachusetts; Cardiology Division, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
Brigham and Women's Hospital, Division of Cardiovascular Medicine, Department of Medicine, Harvard Medical School, Boston, Massachusetts;
J Appl Physiol (1985). 2016 Mar 15;120(6):711-20. doi: 10.1152/japplphysiol.00654.2015. Epub 2015 Oct 15.
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. We examined the relationships between statin exposure, in vitro and in vivo muscle contraction, and expression of candidate circulating myomiRs. We measured plasma levels of myomiRs, circulating microRNA-1 (c-miR-1), c-miR-133a, c-miR-206, and c-miR-499-5p from 28 statin-using and 28 nonstatin-using runners before (PRE), immediately after (FINISH), and 24 h after they ran a 42-km footrace (the 2011 Boston marathon) (POST-24). To examine these cellular-regulation myomiRs, we used contracting mouse C2C12 myotubes in culture with and without statin exposure to compare intracellular and extracellular expression of these molecules. 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 but increased at POST-24 among statin users compared with PRE and runners who did not take statins. In cultured C2C12 myotubes, extracellular c-miR-1, c-miR-133a, and c-miR-206 were significantly increased by muscle contraction regardless of statin use. In contrast, extracellular miR-499-5p was unaffected by either isolated statin exposure or isolated carbachol exposure but it was increased when muscle contraction was combined with statin exposure. In summary, we found that statin-potentiated muscle injury during exercise is accompanied by augmented extracellular release of miR-499-5p. Thus c-miR-499-5p may serve as a biomarker of statin-potentiated muscle damage.
他汀类药物会加剧运动引起的骨骼肌损伤。长时间运动后，肌肉特异性微小RNA（肌微小RNA）在血浆中的水平会升高，但他汀类药物相关肌肉损伤后肌微小RNA的释放模式尚未得到研究。我们研究了他汀类药物暴露、体内外肌肉收缩与候选循环肌微小RNA表达之间的关系。我们测量了28名服用他汀类药物的跑步者和28名未服用他汀类药物的跑步者在参加42公里赛跑（2011年波士顿马拉松赛）前（PRE）、刚跑完后（FINISH）以及跑完24小时后（POST - 24）血浆中肌微小RNA、循环微小RNA - 1（c - miR - 1）、c - miR - 133a、c - miR - 206和c - miR -499 - 5p的水平。为了研究这些细胞调节性肌微小RNA，我们在有或没有他汀类药物暴露的情况下，使用培养的收缩小鼠C2C12肌管来比较这些分子在细胞内和细胞外的表达。在马拉松运动员中，c - miR - 1、c - miR - 133a和c - miR - 206在FINISH时升高，在POST - 24时恢复到基线水平，且不受他汀类药物使用的影响。相比之下，c - miR - 499 - 5p在FINISH时没有变化，但在POST - 24时，与PRE相比，服用他汀类药物的跑步者以及未服用他汀类药物的跑步者中，其水平升高。在培养的C2C12肌管中，无论是否使用他汀类药物，肌肉收缩都会显著增加细胞外c - miR - 1、c - miR - 133a和c - miR - 206的水平。相比之下，细胞外miR - 499 - 5p既不受单独的他汀类药物暴露影响，也不受单独的卡巴胆碱暴露影响，但当肌肉收缩与他汀类药物暴露同时存在时，其水平会升高。总之，我们发现运动期间他汀类药物加剧的肌肉损伤伴随着miR - 499 - 5p细胞外释放的增加。因此，c - miR - 499 - 5р可能作为他汀类药物加剧肌肉损伤的生物标志物。
