Aging-associated genes and let-7 microRNAs: a contribution to myogenic program dysregulation in oculopharyngeal muscular dystrophy
Aging-associated genes and let-7 microRNAs: a contribution to myogenic program dysregulation in oculopharyngeal muscular dystrophy
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DOI：
10.1096/fj.201801577rr
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发表时间：
2019-06-01
期刊：
影响因子：
4.8
通讯作者：
Mantegazza, Renato
中科院分区：
文献类型：
--
作者：
Cappelletti, Cristina;Galbardi, Barbara;Mantegazza, Renato
眼咽肌营养不良症（OPMD）是一种迟发性肌肉疾病，由多聚腺苷酸结合蛋白核1基因内的异常（GCN）三联体扩增以及随后的mRNA加工障碍和肌源性缺陷引起。由于细胞增殖潜力降低和随之而来的衰老肌肉再生失败已被证明是由致死-7（let-7）microRNA介导的机制所控制的，因此在本研究中，我们评估了let-7在OPMD发病机制中的作用。通过多学科的方法，包括共聚焦显微镜，蛋白质印迹和定量PCR分析患者和未受影响的个人的肌肉活检，我们发现了一个显着增加，让7表达OPMD肌肉与一个不寻常的高比例的配对盒7阳性卫星细胞。此外，IL-6，参与卫星细胞增殖和分化的调节和let-7的潜在目标的细胞因子，被发现强烈下调OPMD相比，控制肌肉。在患者和对照组肌细胞分化过程中，IL-6转录水平和蛋白质含量的降低也在体外得到证实。总的来说，我们的数据表明let-7在OPMD肌肉的再生和变性过程中起着关键作用，并指出IL-6是这种疾病新治疗方法的潜在靶分子。卡佩莱蒂角，Galbardi，B.，Bruttini，M.，萨莱诺，F.，Canioni，E.，帕萨尼西湾B.，Rodolico角，Brizzi，T.，莫拉，M.，Renieri，A.，马吉湖，Bernasconi，P.，曼特加扎河衰老相关基因和let-7 microRNAs：眼咽型肌营养不良症中肌源性程序失调的贡献
Oculopharyngeal muscular dystrophy (OPMD) is a late-onset muscle disease caused by an abnormal (GCN) triplet expansion within the polyadenylate-binding protein nuclear 1 gene and consequent mRNA processing impairment and myogenic defects. Because a reduced cell proliferation potential and the consequent regeneration failure of aging muscle have been shown to be governed by lethal-7 (let-7) microRNA-mediated mechanisms, in the present study, we evaluated the role of let-7 in the pathogenesis of OPMD. By a multidisciplinary approach, including confocal microscopy, Western blot, and quantitative PCR analyses on muscle biopsies from patients and unaffected individuals, we found a significant increase in let-7 expression in OPMD muscles associated with an unusual high percentage of paired box 7-positive satellite cells. Furthermore, IL-6, a cytokine involved in the regulation of satellite cell proliferation and differentiation and a potential target of let-7, was found strongly down-regulated in OPMD compared with control muscles. The decrease in IL-6 transcript levels and protein content was also confirmed in vitro during differentiation of patients' and controls' muscle cells. Overall, our data suggest a key role of let-7 in the regeneration and degeneration process in OPMD muscle and pointed to IL-6 as a potential target molecule for new therapeutic approaches for this disorder.-Cappelletti, C., Galbardi, B., Bruttini, M., Salerno, F., Canioni, E., Pasanisi, M. B., Rodolico, C., Brizzi, T., Mora, M., Renieri, A., Maggi, L., Bernasconi, P., Mantegazza, R. Aging-associated genes and let-7 microRNAs: a contribution to myogenic program dysregulation in oculopharyngeal muscular dystrophy.