Department of Neurology, Osaka University Graduate School of Medicine, Suita 565-0871, Osaka, Japan.
Int J Mol Sci. 2022 Feb 20;23(4):2339. doi: 10.3390/ijms23042339.
Myotonic dystrophy (DM) is a dominantly inherited multisystemic disorder affecting various organs, such as skeletal muscle, heart, the nervous system, and the eye. Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are caused by expanded CTG and CCTG repeats, respectively. In both forms, the mutant transcripts containing expanded repeats aggregate as nuclear foci and sequester several RNA-binding proteins, resulting in alternative splicing dysregulation. Although certain alternative splicing events are linked to the clinical DM phenotypes, the molecular mechanisms underlying multiple DM symptoms remain unclear. Interestingly, multi-systemic DM manifestations, including muscle weakness, cognitive impairment, cataract, and frontal baldness, resemble premature aging. Furthermore, cellular senescence, a critical contributor to aging, is suggested to play a key role in DM cellular pathophysiology. In particular, several senescence inducers including telomere shortening, mitochondrial dysfunction, and oxidative stress and senescence biomarkers such as cell cycle inhibitors, senescence-associated secretory phenotype, chromatin reorganization, and microRNA have been implicated in DM pathogenesis. In this review, we focus on the clinical similarities between DM and aging, and summarize the involvement of cellular senescence in DM and the potential application of anti-aging DM therapies.
强直性肌营养不良症 (DM) 是一种显性遗传性多系统疾病，影响多种器官，如骨骼肌、心脏、神经系统和眼睛。1 型和 2 型强直性肌营养不良症分别由扩展的 CTG 和 CCTG 重复引起。在这两种形式中，含有扩展重复的突变转录本聚集成核焦点，并隔离几种 RNA 结合蛋白，导致选择性剪接失调。尽管某些选择性剪接事件与临床 DM 表型相关，但多系统 DM 症状的分子机制仍不清楚。有趣的是，多系统 DM 表现，包括肌肉无力、认知障碍、白内障和额秃，类似于早衰。此外，细胞衰老作为衰老的关键贡献者，被认为在 DM 细胞病理生理学中发挥关键作用。特别是，几种衰老诱导剂，包括端粒缩短、线粒体功能障碍和氧化应激以及衰老生物标志物，如细胞周期抑制剂、衰老相关分泌表型、染色质重排和 microRNA，都与 DM 发病机制有关。在这篇综述中，我们重点关注 DM 和衰老之间的临床相似性，并总结细胞衰老在 DM 中的作用以及抗衰老 DM 疗法的潜在应用。
