Calcitriol increases MBNL1 expression and alleviates myotonic dystrophy phenotypes in HSA(LR) mouse models.
Calcitriol increases MBNL1 expression and alleviates myotonic dystrophy phenotypes in HSA(LR) mouse models.
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DOI：
10.1186/s12967-022-03806-9
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发表时间：
2022-12-12
影响因子：
7.4
通讯作者：
Qiu, Jian
中科院分区：
文献类型：
--
作者：
Huang, Kun;Wang, Dan-Dan;Hu, Wen-Bao;Zeng, Wei-Qian;Xu, Xia;Li, Qiu-Xiang;Bi, Fang-Fang;Yang, Huan;Qiu, Jian
强直性肌营养不良1型（Myotonic dystrophy type 1，DM 1）是成人型肌营养不良症最常见的类型之一，是由DMPK基因3′端非翻译区CTG重复序列异常扩增引起的。从扩增的CTG重复序列转录的CUG重复序列隔离剪接因子MBNL 1，导致DM 1的临床症状。目前，DM 1的治疗方法仅限于对症治疗，尚缺乏合理的治疗方法。最近，MBNL 1表达的上调已被发现是DM 1的有希望的疗法之一。所有实验均在C2 C12成肌细胞和HSALR小鼠（DM 1小鼠模型）中进行。实时荧光定量PCR和蛋白质印迹法分别检测mRNA和蛋白质水平。采用转棒运动、握力和悬吊时间评价小鼠的肌力。在这项研究中，我们证明了维生素D3的活性形式骨化三醇增加了C2 C12小鼠成肌细胞以及HSALR小鼠DM 1模型中的MBNL 1。在HSALR小鼠模型中，骨化三醇改善肌肉力量，并纠正骨骼肌中的异常剪接。骨化三醇还能减少HSALR小鼠中枢神经核团的数量，改善肌肉组织病理学。此外，我们发现骨化三醇通过激活C2 C12肌源性细胞中Mbnl 1的启动子来上调MBNL 1的表达。我们的研究表明，骨化三醇是一种潜在的药理学策略DM 1，增强MBNL 1的表达。在线版本包含补充材料，可通过10.1186/s12967-022-03806-9获得。
Myotonic dystrophy type 1 (DM1), one of the most common forms of adult-onset muscular dystrophy, is caused by abnormally expanded CTG repeats in the 3′ untranslated region of the DMPK gene. The CUG repeats transcribed from the expanded CTG repeats sequestrate a splicing factor, MBNL1, causing the clinical symptoms in DM1. Nowadays, only symptomatic treatments are available for DM1, and no rational therapy is available. Recently, upregulation of MBNL1 expression has been found to be one of the promising therapies for DM1. All experiments were conducted in the C2C12 myoblasts and HSALR mice, a DM1 mouse model. Real-time PCR and western blot were used to detect the mRNA and protein level, respectively. The rotarod exercise, grip strength and hanging time were used to evaluate the muscle strength of mice. In this study, we demonstrated that calcitriol, an active form of vitamin D3, increased MBNL1 in C2C12 mouse myoblasts as well as in HSALR mice model for DM1. In HSALR mice model, calcitriol improved muscle strength, and corrected aberrant splicing in skeletal muscle. Besides, calcitriol reduced the number of central nuclei, and improved muscle histopathology in HSALR mice. In addition, we identified that calcitriol upregulated MBNL1 expression via activating the promoter of Mbnl1 in C2C12 myogenic cells. Our study suggests that calcitriol is a potential pharmacological strategy for DM1 that enhances MBNL1 expression. The online version contains supplementary material available at 10.1186/s12967-022-03806-9.
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影响因子：
7.7
作者：
Ganassi M;Badodi S;Wanders K;Zammit PS;Hughes SM
通讯作者：
Hughes SM
肌肉闪烁的丧失1导致心脏病理和胚胎剪接同工型的持久性。
影响因子：
4.6
作者：
Dixon DM;Choi J;El-Ghazali A;Park SY;Roos KP;Jordan MC;Fishbein MC;Comai L;Reddy S
通讯作者：
Reddy S
影响因子：
3.4
作者：
Alexander MS;Hightower RM;Reid AL;Bennett AH;Iyer L;Slonim DK;Saha M;Kawahara G;Kunkel LM;Kopin AS;Gupta VA;Kang PB;Draper I
通讯作者：
Draper I
影响因子：
14.9
作者：
Konieczny P;Stepniak-Konieczna E;Taylor K;Sznajder LJ;Sobczak K
通讯作者：
Sobczak K
影响因子：
3.7
作者：
Bargiela A;Llamusi B;Cerro-Herreros E;Artero R
通讯作者：
Artero R