Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 5B2, Canada.
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
Int J Mol Sci. 2023 Feb 14;24(4):3794. doi: 10.3390/ijms24043794.
Myotonic dystrophy type 1 (DM1), the most common form of adult muscular dystrophy, is caused by an abnormal expansion of CTG repeats in the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The expanded repeats of the DMPK mRNA form hairpin structures in vitro, which cause misregulation and/or sequestration of proteins including the splicing regulator muscleblind-like 1 (MBNL1). In turn, misregulation and sequestration of such proteins result in the aberrant alternative splicing of diverse mRNAs and underlie, at least in part, DM1 pathogenesis. It has been previously shown that disaggregating RNA foci repletes free MBNL1, rescues DM1 spliceopathy, and alleviates associated symptoms such as myotonia. Using an FDA-approved drug library, we have screened for a reduction of CUG foci in patient muscle cells and identified the HDAC inhibitor, vorinostat, as an inhibitor of foci formation; SERCA1 (sarcoplasmic/endoplasmic reticulum Ca-ATPase) spliceopathy was also improved by vorinostat treatment. Vorinostat treatment in a mouse model of DM1 (human skeletal actin-long repeat; HSA) improved several spliceopathies, reduced muscle central nucleation, and restored chloride channel levels at the sarcolemma. Our in vitro and in vivo evidence showing amelioration of several DM1 disease markers marks vorinostat as a promising novel DM1 therapy.
肌强直性营养不良 1 型（DM1）是最常见的成人肌肉营养不良症，由肌强直性营养不良蛋白激酶（DMPK）基因 3'非翻译区的 CTG 重复异常扩展引起。DMPK mRNA 的扩展重复在体外形成发夹结构，导致包括剪接调节剂肌肉盲样蛋白 1（MBNL1）在内的蛋白质的错误调节和/或隔离。反过来，这些蛋白质的错误调节和隔离导致各种 mRNA 的异常选择性剪接，并至少部分导致 DM1 发病机制。先前已经表明，解聚 RNA 焦点会补充游离的 MBNL1，挽救 DM1 剪接病，并缓解相关症状，如肌强直。我们使用美国食品和药物管理局批准的药物库筛选患者肌肉细胞中 CUG 焦点的减少，并确定组蛋白去乙酰化酶抑制剂伏立诺他是焦点形成的抑制剂；伏立诺他治疗还改善了 SERCA1（肌浆/内质网 Ca-ATP 酶）剪接病。在 DM1（人类骨骼肌肌动蛋白长重复；HSA）的小鼠模型中，伏立诺他治疗可改善几种剪接病，减少肌肉中心核化，并恢复肌膜上的氯离子通道水平。我们的体外和体内证据表明，几种 DM1 疾病标志物的改善标志着伏立诺他是一种有前途的新型 DM1 治疗方法。
