1. Academic Validation
  2. Calcitriol increases MBNL1 expression and alleviates myotonic dystrophy phenotypes in HSALR mouse models

Calcitriol increases MBNL1 expression and alleviates myotonic dystrophy phenotypes in HSALR mouse models

  • J Transl Med. 2022 Dec 12;20(1):588. doi: 10.1186/s12967-022-03806-9.
Kun Huang 1 2 3 Dan-Dan Wang 1 3 Wen-Bao Hu 1 3 Wei-Qian Zeng 1 3 Xia Xu 4 3 Qiu-Xiang Li 2 3 Fang-Fang Bi 2 3 Huan Yang 2 3 Jian Qiu 5 6 7
Affiliations

Affiliations

  • 1 Hunan Key Laboratory of Molecular Precision Medicine, Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 2 Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 3 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 4 Department of General Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 5 Hunan Key Laboratory of Molecular Precision Medicine, Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China. qiujian@sklmg.edu.cn.
  • 6 Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China. qiujian@sklmg.edu.cn.
  • 7 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China. qiujian@sklmg.edu.cn.
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: Our study suggests that calcitriol is a potential pharmacological strategy for DM1 that enhances MBNL1 expression.

Keywords

Calcitriol; HSALR mouse; MBNL1; Myotonic dystrophy; Neuromuscular disorders.

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