Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA, Dubowitz Neuromuscular Centre, UCL Institute of Child Health, 30 Guildford Street, London, WC1N 1EH, UK and Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Level 3, Women's Centre, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Nucleic Acids Res. 2013 Nov;41(20):9500-13. doi: 10.1093/nar/gkt724. Epub 2013 Aug 14.
Extracellular microRNAs (miRNAs) are promising biomarkers of the inherited muscle wasting condition Duchenne muscular dystrophy, as they allow non-invasive monitoring of either disease progression or response to therapy. In this study, serum miRNA profiling reveals a distinct extracellular miRNA signature in dystrophin-deficient mdx mice, which shows profound dose-responsive restoration following dystrophin rescue. Extracellular dystrophy-associated miRNAs (dystromiRs) show dynamic patterns of expression that mirror the progression of muscle pathology in mdx mice. Expression of the myogenic miRNA, miR-206 and the myogenic transcription factor myogenin in the tibialis anterior muscle were found to positively correlate with serum dystromiR levels, suggesting that extracellular miRNAs are indicators of the regenerative status of the musculature. Similarly, extracellular dystromiRs were elevated following experimentally-induced skeletal muscle injury and regeneration in non-dystrophic mice. Only a minority of serum dystromiRs were found in extracellular vesicles, whereas the majority were protected from serum nucleases by association with protein/lipoprotein complexes. In conclusion, extracellular miRNAs are dynamic indices of pathophysiological processes in skeletal muscle.
细胞外 microRNAs（miRNAs）是杜氏肌营养不良症等遗传性肌肉消耗疾病有前途的生物标志物，因为它们可以非侵入性地监测疾病进展或对治疗的反应。在这项研究中，血清 miRNA 谱分析揭示了缺乏 dystrophin 的 mdx 小鼠中独特的细胞外 miRNA 特征，在肌营养不良蛋白 rescue 后表现出明显的剂量反应恢复。细胞外与肌营养不良相关的 miRNAs（dystromiRs）表现出与 mdx 小鼠肌肉病理学进展相吻合的动态表达模式。在比目鱼肌中，肌源性 miRNA miR-206 和肌源性转录因子 myogenin 的表达与血清 dystromiR 水平呈正相关，表明细胞外 miRNAs 是肌肉再生状态的指标。同样，在非肌营养不良小鼠的实验性骨骼肌损伤和再生后，细胞外 dystromiRs 水平升高。只有少数血清 dystromiRs 存在于细胞外囊泡中，而大多数则通过与蛋白/脂蛋白复合物结合免受血清核酸酶的影响。总之，细胞外 miRNAs 是骨骼肌肉病理生理过程的动态指标。
