Vitamin D - vitamin D receptor axis affects muscle differentiation and improves muscle regeneration

2019 Fiscal Year Annual Research Report

• Project/Area Number: 18K16236
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: MARIA TSOUMPRA 国立研究開発法人国立精神・神経医療研究センター, 神経研究所 遺伝子疾患治療研究部, 科研費研究員 (80756198)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: vitamin D / vitamin D receptor / dystrobrevin / dystrophin / muscle

Outline of Annual Research Achievements

活性型ビタミンDの一種である1,25-水酸化ビタミンD3(VD3)は、核内受容体の一つであるビタミンD受容体(VDR)に結合し、このVDRはレチノイドX受容体(RXR)とヘテロ二量体を形成し、標的遺伝子のビタミンD応答配列(vitamin D response element: VDRE)に結合することにより遺伝子発現を調節する。VD3投与により、マウスの骨格筋細胞の筋原性因子の転写調節とともにVDRの発現亢進がおこることから、VD3は筋肉に有益な作用を有すると想定される。本研究では、ジストロフィン類似蛋白であるアルファジストロブレビン(Dtna)発現調節におけるVD3/VDR系の作用を解明した。C2C12細胞や筋ジストロフィーモデル動物由来のH2K-mdx52細胞において、VD3はDtnaやVDR遺伝子、蛋白の発現を促進した。部位特異的変異誘発とクロマチン免疫沈降法により、マウスDtna遺伝子筋肉特異的プロモーターにVDREを同定し、VD3がVDR依存性に本プロモーター活性を促進することを見出した。本研究により、VDR依存性のDtna発現調節機構が明らかとなった。本成果は、骨格筋疾患においてジストロフィン結合蛋白複合体を安定化させることを目的とする治療の開発に役立つ可能性がある。

Research Products

• [Journal Article] Dystrobrevin alpha gene is a direct target of the vitamin D receptor in muscle (2020)
  • Author(s): Tsoumpra MK, Sawatsubashi S, Imamura M, Fukumoto S, Takeda S, Matsumoto T, Aoki Y.
  • Journal Title: J Mol Endocrinololy Volume: 64 Pages: 195-208
  • DOI: 10.1530/JME-19-0229
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] How do we sense phosphate to regulate serum phosphate level? (2019)
  • Author(s): Fukumoto S, Takashi Y, Tsoumpra MK, Sawatsubashi S, Matsumoto T.
  • Journal Title: J Bone Miner Metabolism Volume: 38 Pages: 1-6
  • DOI: 10.1007/s00774-019-01066-0
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Peptide-conjugate antisense based splice-correction for Duchenne muscular dystrophy and other neuromuscular diseases (2019)
  • Author(s): Tsoumpra MK, Fukumoto S, Matsumoto T, Takeda S, Wood MJA, Aoki Y.
  • Journal Title: EBioMedicine Volume: 45 Pages: 630-645
  • DOI: 10.1016/j.ebiom.2019.06.036
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Activation of unliganded FGF receptor by extracellular phosphate potentiates proteolytic protection of FGF23 by its O-glycosylation (2019)
  • Author(s): Takashi Y, Kosako H, Sawatsubashi S, Kinoshita Y, Ito N, Tsoumpra MK, Nangaku M, Abe M, Matsuhisa M, Kato S, Matsumoto T, Fukumoto S.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 116 Pages: 11418-11427
  • DOI: 10.1073/pnas.1815166116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Dual PPMO combinations drive multi-exon skipping and dystrophin expression in CXMDJ (2019)
  • Author(s): Maria K. Tsoumpra, Loïc Roux, Graham McClorey, Mutsuki Kuraoka, Sayuri Arima, Yoshitaka Mizobe, Yuko Hara, Andrey A. Arzumanov, Michael J. Gait, Koichi Kimura, Michihiro Imamura, Shin’ichi Takeda, Toshifumi Yokota, Caroline Godfrey, Matthew A. Wood, and Yoshitsugu Aoki
  • Organizer: ASAS-Japanese muscle society
  • Invited
• [Presentation] Novel peptide-conjugated morpholino oligomer (PPMO) combinations induce multi-exon skipping and dystrophin restoration in the beagle-based canine X-linked muscular dystrophy (CXMDJ) dog model (2019)
  • Author(s): Maria K. Tsoumpra, Graham McClorey, Mutsuki Kuraoka, Yoshitaka Mizobe, Yuko Hara, Andrey A. Arzumanov, Michihiro Imamura, Michael J. Gait, Shin’ichi Takeda, Toshifumi Yokota, Matthew A. Wood and Yoshitsugu Aoki
  • Organizer: European Myology Meeting
  • Int'l Joint Research
• [Presentation] The Vitamin D- Vitamin D Receptor Axis Positively Regulates the Expression of Dystrobrevin Alpha During Murine Myogenic Differentiation (2019)
  • Author(s): Maria K. Tsoumpra, Michihiro Imamura, Yoshitaka Mizobe, Shin’ichi Takeda, Seiji Fukumoto, Toshio Matsumoto and Yoshitsugu Aoki
  • Organizer: American Society Bone Mineral Research
  • Int'l Joint Research
• [Presentation] The member of dystrophin associated protein complex dystrobrevin alpha, is a direct target of vitamin D (2019)
  • Author(s): Maria K. Tsoumpra, Michihiro Imamura, Yoshitaka Mizobe, Shin’ichi Takeda, Seiji Fukumoto, Toshio Matsumoto and Yoshitsugu Aoki
  • Organizer: Annual Molecular Biology Meeting (MBSJ)
• [Presentation] The vitamin D/vitamin D receptor axis positively regulates the expression of dystrobrevin alpha during murine myogenic differentiation (2019)
  • Author(s): Maria K. Tsoumpra, Michihiro Imamura, Yoshitaka Mizobe, Shin’ichi Takeda, Seiji Fukumoto, Toshio Matsumoto, Yoshitsugu Aoki
  • Organizer: Vitamin D workshop, Japan