State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center, Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study and the Medical School, Nanjing University, Nanjing, China.
Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development at the School of Life Sciences of Fudan University, Shanghai, China; Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
J Biol Chem. 2020 Jun 26;295(26):8656-8667. doi: 10.1074/jbc.RA119.010839. Epub 2020 Apr 29.
Mutations in the myotubularin 1 () gene can cause the fatal disease X-linked centronuclear myopathy (XLCNM), but the underlying mechanism is incompletely understood. In this report, using an 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 (), in XLCNM skeletal muscle. To assess the role of miR-199a-1 in XLCNM, we crossed with mice and found that the resultant double-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-regulates expression 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.
肌小管素 1 （）基因突变可导致致命性疾病 X 连锁中轴核肌病（XLCNM），但其潜在机制尚不完全清楚。在本报告中，我们使用疾病模型发现，XLCNM 骨骼肌中，内源性 microRNA miR-199a-1 的表达与它的宿主基因 dynamin 2（）一起上调。为了评估 miR-199a-1 在 XLCNM 中的作用，我们将 与 小鼠杂交，发现产生的 双重敲除小鼠表现出健康状况改善的标志，其寿命延长了 30%，肌肉力量和组织学得到改善。机制分析表明，miR-199a-1 直接靶向非肌肉肌球蛋白 IIA（NM IIA）的表达，从而抑制肌肉出生后的发育和成熟。进一步的分析表明，信号转导和转录激活因子 3（STAT3）的表达增加和磷酸化可上调 XLCNM 肌肉中的 表达。我们的结果表明，miR-199a-1 在 XLCNM 病理学中具有关键作用，并暗示该 microRNA 可能成为治疗 XLCNM 的靶点。
