Drug Safety Research Labs, Astellas Pharma Inc.
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University.
J Toxicol Sci. 2020;45(8):503-513. doi: 10.2131/jts.45.503.
Creatine kinase (CK) and lactate dehydrogenase (LDH) serve as biomarkers for skeletal muscle injury in preclinical toxicity studies, but have a limitation regarding tissue specificity. Circulating miR-206 was recently reported to be a useful biomarker for skeletal muscle disorders in humans. Here, we sought to determine whether serum miR-206 can be used as a biomarker in preclinical toxicity studies to detect drug-induced skeletal muscle injury with higher sensitivity and specificity than the biomarkers CK, LDH, skeletal troponin I (sTnI), and myosin light chain 3 (Myl3). We established rat models of skeletal muscle injury through treatment with the muscle toxicant 2,3,5,6-tetramethyl-p-phenylenediamine (TMPD) as well as four in-house compounds. We found that serum miR-206 levels significantly increased after treatment with TMPD, and tended to be higher in rats treated with in-house compounds than in control rats. ROC analysis revealed that the specificity of serum miR-206 for detection of skeletal muscle injury was higher compared with those of other markers. Further, serum miR-206 levels were unchanged in rats with isoproterenol-induced cardiotoxicity. These findings demonstrate that serum miR-206 may serve as a highly specific biomarker for preclinical analysis of rats with drug-induced skeletal muscle injuries.
肌酸激酶（CK）和乳酸脱氢酶（LDH）是临床前毒性研究中骨骼肌损伤的生物标志物，但它们在组织特异性方面存在局限性。最近有研究报道，循环 miR-206 是人类骨骼肌疾病的一种有用的生物标志物。在这里，我们试图确定血清 miR-206 是否可以作为临床前毒性研究中的一种生物标志物，以比 CK、LDH、骨骼肌肌钙蛋白 I（sTnI）和肌球蛋白轻链 3（Myl3）等生物标志物更高的灵敏度和特异性来检测药物引起的骨骼肌损伤。我们通过用肌肉毒物 2,3,5,6-四甲基-对苯二胺（TMPD）以及四种内部化合物处理大鼠来建立骨骼肌损伤模型。我们发现，TMPD 处理后血清 miR-206 水平显著升高，且在接受内部化合物处理的大鼠中比在对照大鼠中更高。ROC 分析显示，血清 miR-206 检测骨骼肌损伤的特异性高于其他标志物。此外，异丙肾上腺素引起的心肌毒性大鼠的血清 miR-206 水平没有变化。这些发现表明，血清 miR-206 可能是一种用于临床前分析药物诱导的大鼠骨骼肌损伤的高度特异性生物标志物。
