Anhui Provincial Key Laboratory of Molecular Enzymology and Mechanism of Major Diseases, College of Life Sciences, Anhui Normal University, Wuhu, China.
Anhui Provincial Key Laboratory of the Conservation and Exploitation of Biological Resources, College of Life Sciences, Anhui Normal University, Wuhu, China.
Front Endocrinol (Lausanne). 2022 Apr 7;13:843202. doi: 10.3389/fendo.2022.843202. eCollection 2022.
Myotonic dystrophy type 1 (DM1) is caused by the expanded CUG repeats and usually displays defective myogenesis. Although we previously reported that ectopic miR-322/-503 expression improved myogenesis in DM1 by targeting the toxic RNA, the underlying pathways regulating myogenesis that were aberrantly altered in DM1 and rescued by miR-322/-503 were still unknown. Here, we constructed DM1 and miR-322/-503 overexpressing DM1 myoblast models, which were subjected to myoblast differentiation along with their corresponding controls. Agreeing with previous findings, DM1 myoblast showed remarkable myogenesis defects, while miR-322/-503 overexpression successfully rescued the defects. By RNA sequencing, we noticed that Tumor necrosis factor (TNF) signaling was the only pathway that was significantly and oppositely altered in these two experimental sets, with it upregulated in DM1 and inhibited by miR-322/-503 overexpression. Consistently, hyperactivity of TNF signaling was detected in two DM1 mouse models. Blocking TNF signaling significantly rescued the myogenesis defects in DM1. On the contrary, TNF-α treatment abolished the rescue effect of miR-322/-503 on DM1 myogenesis. Taking together, these results implied that TNF signaling mediated the myogenesis defects in DM1 and might act downstream of miR-322/-503 in regulating the myogenesis in DM1. Moreover, the inhibition of TNF signaling benefiting myogenesis in DM1 provided us with a novel therapeutic strategy for DM1.
肌强直性营养不良 1 型（DM1）是由 CUG 重复扩展引起的，通常表现为肌生成缺陷。虽然我们之前报道过异位 miR-322/-503 表达通过靶向毒性 RNA 改善 DM1 中的肌生成，但 DM1 中异常改变并被 miR-322/-503 挽救的调节肌生成的潜在途径仍不清楚。在这里，我们构建了 DM1 和 miR-322/-503 过表达 DM1 成肌细胞模型，这些模型与相应的对照一起进行成肌细胞分化。与之前的发现一致，DM1 成肌细胞表现出明显的肌生成缺陷，而 miR-322/-503 过表达成功挽救了这些缺陷。通过 RNA 测序，我们注意到肿瘤坏死因子 (TNF) 信号通路是这两个实验组中唯一显著且相反改变的通路，该通路在 DM1 中上调，并被 miR-322/-503 过表达抑制。一致地，在两种 DM1 小鼠模型中检测到 TNF 信号的过度激活。阻断 TNF 信号显著挽救了 DM1 中的肌生成缺陷。相反，TNF-α 处理消除了 miR-322/-503 对 DM1 肌生成的挽救作用。综上所述，这些结果表明 TNF 信号介导了 DM1 中的肌生成缺陷，并且可能在调节 DM1 中的肌生成中作为 miR-322/-503 的下游发挥作用。此外，抑制 TNF 信号有利于 DM1 中的肌生成，为 DM1 提供了一种新的治疗策略。
