Myotonic dystrophy type 1 (DM1) is the most prevalent form of muscular dystrophy in adults and yet there are currently no treatment options. Although this disease causes multisystemic symptoms, it is mainly characterised by myopathy or diseased muscles, which includes muscle weakness, atrophy, and myotonia, severely affecting the lives of patients worldwide. On a molecular level, DM1 is caused by an expansion of CTG repeats in the 3' untranslated region (3'UTR) of the DM1 Protein Kinase (DMPK) gene which become pathogenic when transcribed into RNA forming ribonuclear foci comprised of auto complementary CUG hairpin structures that can bind proteins. This leads to the sequestration of the muscleblind-like (MBNL) family of proteins, depleting them, and the abnormal stabilisation of CUGBP Elav-like family member 1 (CELF1), enhancing it. Traditionally, DM1 research has focused on this RNA toxicity and how it alters MBNL and CELF1 functions as key splicing regulators. However, other proteins are affected by the toxic DMPK RNA and there is strong evidence that supports various signalling cascades playing an important role in DM1 pathogenesis. Specifically, the impairment of protein kinase B (AKT) signalling in DM1 increases autophagy, apoptosis, and ubiquitin-proteasome activity, which may also be affected in DM1 by AMP-activated protein kinase (AMPK) downregulation. AKT also regulates CELF1 directly, by affecting its subcellular localisation, and indirectly as it inhibits glycogen synthase kinase 3 beta (GSK3β), which stabilises the repressive form of CELF1 in DM1. Another kinase that contributes to CELF1 mis-regulation, in this case by hyperphosphorylation, is protein kinase C (PKC). Additionally, it has been demonstrated that fibroblast growth factor-inducible 14 (Fn14) is induced in DM1 and is associated with downstream signalling through the nuclear factor κB (NFκB) pathways, associating inflammation with this disease. Furthermore, MBNL1 and CELF1 play a role in cytoplasmic processes involved in DM1 myopathy, altering proteostasis and sarcomere structure. Finally, there are many other elements that could contribute to the muscular phenotype in DM1 such as alterations to satellite cells, non-coding RNA metabolism, calcium dysregulation, and repeat-associated non-ATG (RAN) translation. This review aims to organise the currently dispersed knowledge on the different pathways affected in DM1 and discusses the unexplored connections that could potentially help in providing new therapeutic targets in DM1 research.

中文翻译：

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肌强直性营养不良 1 型肌肉功能障碍的特征

肌强直性营养不良 1 型 (DM1) 是成人中最普遍的肌营养不良症，但目前尚无治疗选择。该病虽然引起多系统症状，但主要表现为肌病或肌肉病变，包括肌无力、萎缩和肌强直，严重影响全球患者的生活。在分子水平上，DM1 是由 DM1 蛋白激酶 (DMPK) 基因的 3' 非翻译区 (3'UTR) 中 CTG 重复序列的扩展引起的，当转录成 RNA 时会变得致病，形成由自动互补 CUG 发夹组成的核糖核病灶可以结合蛋白质的结构。这导致肌肉盲样 (MBNL) 蛋白家族的隔离，消耗它们，以及 CUGBP Elav 样家族成员 1 (CELF1) 的异常稳定，增强它。传统上，DM1 研究集中在这种 RNA 毒性以及它如何改变 MBNL 和 CELF1 作为关键剪接调节因子的功能。然而，其他蛋白质受到有毒 DMPK RNA 的影响，并且有强有力的证据支持各种信号级联在 DM1 发病机制中发挥重要作用。具体而言，DM1 中蛋白激酶 B (AKT) 信号传导受损会增加自噬、细胞凋亡和泛素蛋白酶体活性，这也可能在 DM1 中受到 AMP 活化蛋白激酶 (AMPK) 下调的影响。AKT 还通过影响 CELF1 的亚细胞定位直接调节 CELF1，并间接调节糖原合酶激酶 3β（GSK3β），后者稳定 DM1 中 CELF1 的抑制形式。另一种导致 CELF1 错误调节的激酶，在这种情况下是通过过度磷酸化，是蛋白激酶 C (PKC)。此外，已经证明成纤维细胞生长因子诱导型 14 (Fn14) 在 DM1 中被诱导，并且与通过核因子 κB (NFκB) 通路的下游信号传导相关，从而将炎症与这种疾病联系起来。此外，MBNL1 和 CELF1 在参与 DM1 肌病的细胞质过程中发挥作用，改变蛋白质稳态和肌节结构。最后，还有许多其他因素可能有助于 DM1 中的肌肉表型，例如卫星细胞的改变、非编码 RNA 代谢、钙失调和重复相关的非 ATG (RAN) 翻译。