The intragenic microRNA miR199A1 in the dynamin 2 gene contributes to the pathology of X-linked centronuclear myopathy
The intragenic microRNA miR199A1 in the dynamin 2 gene contributes to the pathology of X-linked centronuclear myopathy
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dynamin 2 基因中的基因内 microRNAmiR199A1 有助于 X 连锁中心核肌病的病理学
DOI：
10.1074/jbc.ra119.010839
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发表时间：
2020-06-26
影响因子：
4.8
通讯作者：
Zhu, Min-Sheng
中科院分区：
文献类型：
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作者：
Chen, Xin;Gao, Yun-Qian;Zhu, Min-Sheng
肌管蛋白1（MTM 1）基因突变可导致致命性疾病X连锁中枢性肌病（XLCNM），但其潜在机制尚不完全清楚。在本报告中，使用一个Mtm 1（？/ y）疾病模型中，我们发现在XLCNM骨骼肌中基因内microRNA miR-199 a-1的表达与其宿主基因发动蛋白2（Dnm 2）的表达一起沿着上调。为了评估miR-199 a-1在XLCNM中的作用，我们将miR-199 a-1（？/？）在Mtm 1（？/ y）小鼠，并发现所得到的miR-199 a-1-Mtm 1双敲除小鼠显示出健康改善的标志物，如寿命延长30%以及肌肉力量和组织学改善所证明的。机制分析表明，miR-199 a-1直接靶向非肌肉肌球蛋白IIA（NM IIA）的表达，因此，抑制肌肉出生后发育以及肌肉成熟。进一步分析发现，XLCNM肌肉中信号转导子和转录激活子3（STAT 3）的表达增加和磷酸化上调了Dnm 2/miR-199 a-1的表达。我们的研究结果表明，miR-199 a-1在XLCNM病理学中具有关键作用，并意味着这种microRNA可以在治疗中靶向治疗XLCNM。
Mutations in the myotubularin 1 (MTM1) gene can cause the fatal disease X-linked centronuclear myopathy (XLCNM), but the underlying mechanism is incompletely understood. In this report, using anMtm1(?/y)disease model, we found that expression of the intragenic microRNA miR-199a-1 is up-regulated along with that of its host gene, dynamin 2 (Dnm2), in XLCNM skeletal muscle. To assess the role of miR-199a-1 in XLCNM, we crossedmiR-199a-1(?/?)withMtm1(?/y)mice and found that the resultantmiR-199a-1-Mtm1double-knockout mice display markers of improved health, as evidenced by lifespans prolonged by 30% and improved muscle strength and histology. Mechanistic analyses showed that miR-199a-1 directly targets nonmuscle myosin IIA (NM IIA) expression and, hence, inhibits muscle postnatal development as well as muscle maturation. Further analysis revealed that increased expression and phosphorylation of signal transducer and activator of transcription 3 (STAT3) up-regulatesDnm2/miR-199a-1expression in XLCNM muscle. Our results suggest that miR-199a-1 has a critical role in XLCNM pathology and imply that this microRNA could be targeted in therapies to manage XLCNM.