Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
Eric Poulin Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
Hum Mol Genet. 2020 Aug 3;29(13):2185-2199. doi: 10.1093/hmg/ddaa111.
In myotonic dystrophy type 1 (DM1), the CUG expansion (CUGexp) in the 3' untranslated region of the dystrophia myotonica protein kinase messenger ribonucleic acid affects the homeostasis of ribonucleic acid-binding proteins, causing the multiple symptoms of DM1. We have previously reported that Staufen1 is increased in skeletal muscles from DM1 mice and patients and that sustained Staufen1 expression in mature mouse muscle causes a progressive myopathy. Here, we hypothesized that the elevated levels of Staufen1 contributes to the myopathic features of the disease. Interestingly, the classic DM1 mouse model human skeletal actin long repeat (HSALR) lacks overt atrophy while expressing CUGexp transcripts and elevated levels of endogenous Staufen1, suggesting a lower sensitivity to atrophic signaling in this model. We report that further overexpression of Staufen1 in the DM1 mouse model HSALR causes a myopathy via inhibition of protein kinase B signaling through an increase in phosphatase tensin homolog, leading to the expression of atrogenes. Interestingly, we also show that Staufen1 regulates the expression of muscleblind-like splicing regulator 1 and CUG-binding protein elav-like family member 1 in wild-type and DM1 skeletal muscle. Together, data obtained from these new DM1 mouse models provide evidence for the role of Staufen1 as an atrophy-associated gene that impacts progressive muscle wasting in DM1. Accordingly, our findings highlight the potential of Staufen1 as a therapeutic target and biomarker.
在肌强直性营养不良 1 型（DM1）中，抗肌萎缩蛋白激酶信使核糖核酸 3'非翻译区的 CUG 扩展（CUGexp）会影响核糖核酸结合蛋白的内稳态，导致 DM1 的多种症状。我们之前曾报道过，Staufen1 在 DM1 小鼠和患者的骨骼肌中增加，并且持续表达 Staufen1 会导致成熟的小鼠肌肉发生进行性肌病。在这里，我们假设 Staufen1 的升高水平导致了疾病的肌病特征。有趣的是，经典的 DM1 小鼠模型人类骨骼肌肌动蛋白长重复（HSALR）在表达 CUGexp 转录本和升高的内源性 Staufen1 时缺乏明显的萎缩，这表明该模型对萎缩信号的敏感性较低。我们报告说，在 DM1 小鼠模型 HSALR 中进一步过度表达 Staufen1 会通过增加磷酸酶张力蛋白同源物来抑制蛋白激酶 B 信号，从而导致萎缩基因的表达，从而导致肌病。有趣的是，我们还表明 Staufen1 调节野生型和 DM1 骨骼肌中肌肉盲样剪接调节剂 1 和 CUG 结合蛋白 Elav 样家族成员 1 的表达。这些新的 DM1 小鼠模型的数据提供了证据表明，Staufen1 作为一种与萎缩相关的基因，在 DM1 中影响进行性肌肉消耗。因此，我们的发现强调了 Staufen1 作为一种治疗靶点和生物标志物的潜力。
