Department of Neuroscience, Clinical Neurophysiology, Uppsala University, BMC, Husargatan 3, Uppsala, Sweden.
Department of Medical Biochemistry and Microbiology, Uppsala University, BMC Box 582, Uppsala, Sweden.
Neurosci Res. 2020 Feb;151:46-52. doi: 10.1016/j.neures.2019.02.003. Epub 2019 Feb 11.
MuSK antibody seropositive (MuSK+) Myasthenia Gravis (MG) typically affects skeletal muscles of the bulbar area, including the omohyoid muscle, causing focal fatigue, weakness and atrophy. The profile of circulating extracellular microRNA (miRNA) is changed in MuSK + MG, but the intracellular miRNA profile in skeletal muscles of MuSK + MG and MuSK + experimental autoimmune MG (EAMG) remains unknown. This study elucidated the intracellular miRNA profile in the omohyoid muscle of mice with MuSK + EAMG. The levels of eleven mouse miRNAs were elevated and two mouse miRNAs were reduced in muscles of MuSK + EAMG mice. Transient expression of miR-1933-3p and miR-1930-5p in mouse muscle (C2C12) cells revealed several downregulated genes, out of which five had predicted binding sites for miR-1933-3p. The mRNA expression of mitochondrial ribosomal protein L27 (Mrpl27) and Inositol monophosphatase I (Impa1) was reduced in miR-1933-3p transfected C2C12 cells compared to control cells (p = 0.032 versus p = 0.020). Further, transient expression of miR-1933-3p reduced Impa1 protein accumulation in C2C12 cells. These findings provide novel insights of dysregulated miRNAs and their intracellular pathways in muscle tissue afflicted with MuSK + EAMG, providing a possible link to mitochondrial dysfunction and muscle atrophy observed in MuSK + MG.
抗缪勒管激素抗体阳性（MuSK+）重症肌无力（MG）通常影响延髓区域的骨骼肌，包括胸锁乳突肌，导致局部疲劳、无力和萎缩。MuSK+MG 患者循环细胞外 microRNA（miRNA）的特征发生改变，但 MuSK+MG 和 MuSK+实验性自身免疫性重症肌无力（EAMG）骨骼肌中的细胞内 miRNA 特征尚不清楚。本研究阐明了 MuSK+EAMG 小鼠胸锁乳突肌的细胞内 miRNA 特征。MuSK+EAMG 小鼠肌肉中的 11 种小鼠 miRNA 水平升高，两种小鼠 miRNA 水平降低。在小鼠肌肉（C2C12）细胞中转瞬表达 miR-1933-3p 和 miR-1930-5p 揭示了几个下调基因，其中五个基因具有 miR-1933-3p 的预测结合位点。与对照细胞相比，miR-1933-3p 转染的 C2C12 细胞中线粒体核糖体蛋白 L27（Mrpl27）和肌醇单磷酸酶 I（Impa1）的 mRNA 表达降低（p=0.032 对 p=0.020）。此外，miR-1933-3p 的瞬时表达减少了 C2C12 细胞中 Impa1 蛋白的积累。这些发现为 MuSK+EAMG 肌肉组织中失调 miRNA 及其细胞内途径提供了新的见解，为 MuSK+MG 中观察到的线粒体功能障碍和肌肉萎缩提供了可能的联系。
