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Calcitriol ameliorates motor deficits and prolongs survival of Chrne-deficient mouse, a model for congenital myasthenic syndrome, by inducing Rspo2.
Ohkawara, Bisei; Tomita, Hiroyuki; Inoue, Taro; Zhang, Shaochuan; Kanbara, Shunsuke; Koshimizu, Hiroyuki; Miyasaka, Yuki; Takeda, Jun-Ichi; Nishiwaki, Hiroshi; Nakashima, Hiroaki; Ito, Mikako; Masuda, Akio; Ishiguro, Naoki; Ogi, Tomoo; Ohno, Tamio; Imagama, Shiro; Ohno, Kinji.
Afiliación
  • Ohkawara B; Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: biseiohkawara@med.nagoya-u.ac.jp.
  • Tomita H; Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Inoue T; Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Zhang S; Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Kanbara S; Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Koshimizu H; Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Miyasaka Y; Department of Genetics, Research Institute of Environmental Medicine (RIeM), Nagoya University, Nagoya, Japan.
  • Takeda JI; Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Nishiwaki H; Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Nakashima H; Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Ito M; Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Masuda A; Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Ishiguro N; Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Ogi T; Department of Genetics, Research Institute of Environmental Medicine (RIeM), Nagoya University, Nagoya, Japan.
  • Ohno T; Division of Experimental Animals, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Imagama S; Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Ohno K; Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: ohnok@med.nagoya-u.ac.jp.
Neurotherapeutics ; 21(2): e00318, 2024 Mar.
Article en En | MEDLINE | ID: mdl-38233267
ABSTRACT
Signal transduction at the neuromuscular junction (NMJ) is compromised in a diverse array of diseases including congenital myasthenic syndromes (CMS). Germline mutations in CHRNE encoding the acetylcholine receptor (AChR) ε subunit are the most common cause of CMS. An active form of vitamin D, calcitriol, binds to vitamin D receptor (VDR) and regulates gene expressions. We found that calcitriol enhanced MuSK phosphorylation, AChR clustering, and myotube twitching in co-cultured C2C12 myotubes and NSC34 motor neurons. RNA-seq analysis of co-cultured cells showed that calcitriol increased the expressions of Rspo2, Rapsn, and Dusp6. ChIP-seq of VDR revealed that VDR binds to a region approximately 15 â€‹kbp upstream to Rspo2. Biallelic deletion of the VDR-binding site of Rspo2 by CRISPR/Cas9 in C2C12 myoblasts/myotubes nullified the calcitriol-mediated induction of Rspo2 expression and MuSK phosphorylation. We generated Chrne knockout (Chrne KO) mouse by CRISPR/Cas9. Intraperitoneal administration of calcitriol markedly increased the number of AChR clusters, as well as the area, the intensity, and the number of synaptophysin-positive synaptic vesicles, in Chrne KO mice. In addition, calcitriol ameliorated motor deficits and prolonged survival of Chrne KO mice. In the skeletal muscle, calcitriol increased the gene expressions of Rspo2, Rapsn, and Dusp6. We propose that calcitriol is a potential therapeutic agent for CMS and other diseases with defective neuromuscular signal transmission.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndromes Miasténicos Congénitos Límite: Animals Idioma: En Revista: Neurotherapeutics Asunto de la revista: NEUROLOGIA Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndromes Miasténicos Congénitos Límite: Animals Idioma: En Revista: Neurotherapeutics Asunto de la revista: NEUROLOGIA Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos