Translational Genomics Group, Incliva Health Research Institute, 46010 Valencia, Spain.
Interdisciplinary Research Structure for Biotechnology and Biomedicine, University of Valencia, 46100 Valencia, Spain.
Proc Natl Acad Sci U S A. 2019 Dec 10;116(50):25203-25213. doi: 10.1073/pnas.1820297116. Epub 2019 Nov 21.
Myotonic dystrophy type 1 (DM1) is a life-threatening and chronically debilitating neuromuscular disease caused by the expansion of a CTG trinucleotide repeat in the 3' UTR of the gene. The mutant RNA forms insoluble structures capable of sequestering RNA binding proteins of the Muscleblind-like (MBNL) family, which ultimately leads to phenotypes. In this work, we demonstrate that treatment with the antiautophagic drug chloroquine was sufficient to up-regulate MBNL1 and 2 proteins in and mouse (HSA) models and patient-derived myoblasts. Extra Muscleblind was functional at the molecular level and improved splicing events regulated by MBNLs in all disease models. In vivo, chloroquine restored locomotion, rescued average cross-sectional muscle area, and extended median survival in DM1 flies. In HSA mice, the drug restored muscular strength and histopathology signs and reduced the grade of myotonia. Taken together, these results offer a means to replenish critically low MBNL levels in DM1.
肌强直性营养不良 1 型（DM1）是一种危及生命且慢性进行性的神经肌肉疾病，由 基因 3'UTR 中的 CTG 三核苷酸重复扩展引起。突变 RNA 形成不溶性结构，能够隔离肌肉盲样（MBNL）家族的 RNA 结合蛋白，最终导致表型。在这项工作中，我们证明了用抗自噬药物氯喹治疗足以上调 和小鼠（HSA）模型以及患者来源的成肌细胞中的 MBNL1 和 2 蛋白。多余的肌肉盲样在分子水平上是功能性的，并改善了所有疾病模型中由 MBNLs 调节的剪接事件。在体内，氯喹恢复了 DM1 果蝇的运动能力，挽救了平均横截面积，并延长了中位生存期。在 HSA 小鼠中，该药物恢复了肌肉力量和组织病理学迹象，并降低了肌强直的程度。总之，这些结果为补充 DM1 中关键低水平的 MBNL 提供了一种方法。
