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Elucidation of molecular mechanisms of defective neuromuscular signal transmission as a primary cause of sarcopenia

Research Project

Project/Area Number 19K22802
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 59:Sports sciences, physical education, health sciences, and related fields
Research InstitutionNagoya University

Principal Investigator

Ohno Kinji  名古屋大学, 医学系研究科, 教授 (80397455)

Project Period (FY) 2019-06-28 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2020: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Keywordsサルコペニア / 廃用性筋萎縮 / 神経筋接合部 / リボタグマウス / 遺伝子発現プロファイル / 神経筋信号伝達障害
Outline of Research at the Start

サルコペニアと廃用性筋萎縮における神経筋接合部(NMJ)信号伝達障害が一次的な原因として注目されている。サルコペニアモデルマウスの脊髄運動神経細胞とNMJ筋終板(endplate)において、RiboTag mouseを用いた網羅的遺伝子発現プロファイリング解析とSPPLAT法によるproximity proteomics解析を行い、サルコペニアの原因に関わるSMN分子・endplate分子を同定し、CRISPR/Cas9によるノックアウトiPS細胞・ノックアウトマウスの解析により、サルコペニアにおけるNMJ病態を明らかにし新規治療法開発につなげる。

Outline of Final Research Achievements

Accumulating knowledge points to the notion that defects in the neuromuscular signal transmission are potentially the primary cause of amyotrophy including sarcopenia and muscle disuse atrophy. To explore NMJ-specific genes that are responsible for sarcopenia, we performed extensive gene expression profiling of the mouse motor endplate using RiboTag mouse that enables Cre-mediated HA-tagging to a ribosomal protein, RPL22. Analysis of genes expressed at the motor endplate showed that the phosphatidylinositol signaling system and the extracellular matrix receptor interaction, the roles of which at the neuromuscular junction remain to be elucidated, were highly expressed at the motor endplate. Analysis of subsets of these gene sets further revealed that diacylglycerol kinases, phosphatidylinositol kinases, phospholipases, integrins, laminins were enriched at the motor endplate.

Academic Significance and Societal Importance of the Research Achievements

サルコペニアは世界で男女とも10%の有病率と推定されており高齢者のフレイルの最大要因となっている。しかし、サルコペニアは対症療法以外の薬物療法が存在しない「一般的な病気(common disease)」の代表疾患になっている。近年、サルコペニアに認められる神経筋接合部信号伝達障害はサルコペニアに伴う二次的な現象ではなくサルコペニアの一次的な原因の可能性が指摘されてきた。サルコペニアにともなう神経筋接合部の信号伝達障害の病態を明らかにすることによりサルコペニアの新規治療法開発につながることが期待される。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (33 results)

All 2022 2021 2020 2019

All Journal Article (26 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 26 results,  Open Access: 21 results) Presentation (7 results) (of which Int'l Joint Research: 5 results)

  • [Journal Article] Screening of signaling pathways for agrin-induced AChR clustering in C2C12 myotubes2022

    • Author(s)
      Noto K, Ohkawara B, Ishii H, Ito M, Masuda A, Hirata H, Ohno K.
    • Journal Title

      Genes Cells

      Volume: -

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Promethazine downregulates Wnt/β-catenin signaling and increases biomechanical forces of injured Achilles tendon in early stage of healing2022

    • Author(s)
      Sakaguchi T, Miyamoto K, Ohkawara B, Kisimoto Y, Ishizuka S, Hiraiwa H, Imagama S, Ishiguro N, Ohno K.
    • Journal Title

      Am J Sport Med

      Volume: -

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Meclozine Attenuates the MARK Pathway in Mammalian Chondrocytes and Ameliorates FGF2-Induced Bone Hyperossification in Larval Zebrafish2022

    • Author(s)
      Takemoto Genta、Matsushita Masaki、Okamoto Takaaki、Ito Toshinari、Matsuura Yuki、Takashima Chieko、Chen-Yoshikawa Toyofumi Fengshi、Ebi Hiromichi、Imagama Shiro、Kitoh Hiroshi、Ohno Kinji、Hosono Yasuyuki
    • Journal Title

      Frontiers in Cell and Developmental Biology

      Volume: 9 Pages: 694018-694018

    • DOI

      10.3389/fcell.2021.694018

    • NAID

      120007190703

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Meclozine ameliorates skeletal muscle pathology and increases muscle forces in mdx mice2022

    • Author(s)
      Kawamura Yusuke、Hida Tetsuro、Ohkawara Bisei、Matsushita Masaki、Kobayashi Takeshi、Ishizuka Shinya、Hiraiwa Hideki、Tanaka Satoshi、Tsushima Mikito、Nakashima Hiroaki、Ito Kenyu、Imagama Shiro、Ito Mikako、Masuda Akio、Ishiguro Naoki、Ohno Kinji
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 592 Pages: 87-92

    • DOI

      10.1016/j.bbrc.2022.01.003

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Possible Repositioning of an Oral Anti-Osteoporotic Drug, Ipriflavone, for Treatment of Inflammatory Arthritis via Inhibitory Activity of KIAA1199, a Novel Potent Hyaluronidase2022

    • Author(s)
      Koike Hiroshi、Nishida Yoshihiro、Shinomura Tamayuki、Ohkawara Bisei、Ohno Kinji、Zhuo Lisheng、Kimata Koji、Ushida Takahiro、Imagama Shiro
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 23 Issue: 8 Pages: 4089-4089

    • DOI

      10.3390/ijms23084089

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Extremely low-frequency pulses of faint magnetic field induce mitophagy to rejuvenate mitochondria2022

    • Author(s)
      Toda T, Ito M Takeda J, Masuda A, Mino H, Hattori N, Mohri K, Ohno K
    • Journal Title

      Commun Biol

      Volume: -

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Efficacy of salbutamol monotherapy in slow‐channel congenital myasthenic syndrome caused by a novel mutation in CHRND2021

    • Author(s)
      Tawara Nozomu、Yamashita Satoshi、Takamatsu Koutaro、Yamasaki Yoshimune、Mukaino Akihiro、Nakane Shunya、Farshadyeganeh Paniz、Ohno Kinji、Ando Yukio
    • Journal Title

      Muscle & Nerve

      Volume: 63 Issue: 4

    • DOI

      10.1002/mus.27166

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Zonisamide upregulates neuregulin-1 expression and enhances acetylcholine receptor clustering at the in vitro neuromuscular junction2021

    • Author(s)
      Inoue Taro、Ohkawara Bisei、Bushra Samira、Kanbara Shunsuke、Nakashima Hiroaki、Koshimizu Hiroyuki、Tomita Hiroyuki、Ito Mikako、Masuda Akio、Ishiguro Naoki、Imagama Shiro、Ohno Kinji
    • Journal Title

      Neuropharmacology

      Volume: 195 Pages: 108637-108637

    • DOI

      10.1016/j.neuropharm.2021.108637

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] IntSplice2: Prediction of the Splicing Effects of Intronic Single-Nucleotide Variants Using LightGBM Modeling2021

    • Author(s)
      Takeda Jun-ichi、Fukami Sae、Tamura Akira、Shibata Akihide、Ohno Kinji
    • Journal Title

      Frontiers in Genetics

      Volume: 12 Pages: 701076-701076

    • DOI

      10.3389/fgene.2021.701076

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Regulated splicing of large exons is linked to phase‐separation of vertebrate transcription factors2021

    • Author(s)
      Kawachi Toshihiko、Masuda Akio、Yamashita Yoshihiro、Takeda Jun‐ichi、Ohkawara Bisei、Ito Mikako、Ohno Kinji
    • Journal Title

      The EMBO Journal

      Volume: 40 Issue: 22

    • DOI

      10.15252/embj.2020107485

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Secreted Signaling Molecules at the Neuromuscular Junction in Physiology and Pathology2021

    • Author(s)
      Ohkawara Bisei、Ito Mikako、Ohno Kinji
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 5 Pages: 2455-2455

    • DOI

      10.3390/ijms22052455

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hierarchical non-negative matrix factorization using clinical information for microbial communities2021

    • Author(s)
      Abe Ko、Hirayama Masaaki、Ohno Kinji、Shimamura Teppei
    • Journal Title

      BMC Genomics

      Volume: 22 Issue: 1 Pages: 104-104

    • DOI

      10.1186/s12864-021-07401-y

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Desloratadine inhibits heterotopic ossification by suppression of BMP2‐Smad1/5/8 signaling2020

    • Author(s)
      Kusano Taiki、Nakatani Masashi、Ishiguro Naoki、Ohno Kinji、Yamamoto Naoki、Morita Mitsuhiro、Yamada Harumoto、Uezumi Akiyoshi、Tsuchida Kunihiro
    • Journal Title

      Journal of Orthopaedic Research

      Volume: in press Issue: 6 Pages: 11-11

    • DOI

      10.1002/jor.24625

    • Related Report
      2021 Annual Research Report 2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] tRIP-seq Reveals Repression of Premature Polyadenylation by Co-Transcriptional FUS-U1 snRNP Assembly2020

    • Author(s)
      Akio Masuda, Toshihiko Kawachi, Jun-Ichi Takeda, Bisei Ohkawara, Mikako Ito, Kinji Ohno
    • Journal Title

      EMBO Rep.

      Volume: - Issue: 5

    • DOI

      10.15252/embr.201949890

    • NAID

      120006884959

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Congenital myasthenic syndrome?associated agrin variants affect clustering of acetylcholine receptors in a domain-specific manner2020

    • Author(s)
      Ohkawara Bisei、Shen XinMing、Selcen Duygu、Nazim Mohammad、Bril Vera、Tarnopolsky Mark A.、Brady Lauren、Fukami Sae、Amato Anthony A.、Yis Uluc、Ohno Kinji、Engel Andrew G.
    • Journal Title

      JCI Insight

      Volume: 5 Issue: 7

    • DOI

      10.1172/jci.insight.132023

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Meta‐Analysis of Gut Dysbiosis in Parkinson's Disease2020

    • Author(s)
      Nishiwaki Hiroshi、Ito Mikako、Ishida Tomohiro、Hamaguchi Tomonari、Maeda Tetsuya、Kashihara Kenichi、Tsuboi Yoshio、Ueyama Jun、Shimamura Teppei、Mori Hiroshi、Kurokawa Ken、Katsuno Masahisa、Hirayama Masaaki、Ohno Kinji
    • Journal Title

      Movement Disorders

      Volume: 35 Issue: 9 Pages: 1626-1635

    • DOI

      10.1002/mds.28119

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] InMeRF: prediction of pathogenicity of missense variants by individual modeling for each amino acid substitution2020

    • Author(s)
      Takeda Jun-ichi、Nanatsue Kentaro、Yamagishi Ryosuke、Ito Mikako、Haga Nobuhiko、Hirata Hiromi、Ogi Tomoo、Ohno Kinji
    • Journal Title

      NAR Genomics and Bioinformatics

      Volume: 2 Issue: 2 Pages: 1-11

    • DOI

      10.1093/nargab/lqaa038

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] CTGF/CCN2 facilitates LRP4‐mediated formation of the embryonic neuromuscular junction2020

    • Author(s)
      Ohkawara Bisei、Kobayakawa Akinori、Kanbara Shunsuke、Hattori Takako、Kubota Satoshi、Ito Mikako、Masuda Akio、Takigawa Masaharu、Lyons Karen M、Ishiguro Naoki、Ohno Kinji
    • Journal Title

      EMBO reports

      Volume: 21 Issue: 8

    • DOI

      10.15252/embr.201948462

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Zonisamide ameliorates progression of cervical spondylotic myelopathy in a rat model2020

    • Author(s)
      Kanbara Shunsuke、Ohkawara Bisei、Nakashima Hiroaki、Ohta Kyotaro、Koshimizu Hiroyuki、Inoue Taro、Tomita Hiroyuki、Ito Mikako、Masuda Akio、Ishiguro Naoki、Imagama Shiro、Ohno Kinji
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 13138-13138

    • DOI

      10.1038/s41598-020-70068-0

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Gene Expression Profile at the Motor Endplate of the Neuromuscular Junction of Fast-Twitch Muscle2020

    • Author(s)
      Huang Kun、Li Jin、Ito Mikako、Takeda Jun-Ichi、Ohkawara Bisei、Ogi Tomoo、Masuda Akio、Ohno Kinji
    • Journal Title

      Frontiers in Molecular Neuroscience

      Volume: 13 Pages: 154-154

    • DOI

      10.3389/fnmol.2020.00154

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Short-Chain Fatty Acid-Producing Gut Microbiota Is Decreased in Parkinson’s Disease but Not in Rapid-Eye-Movement Sleep Behavior Disorder2020

    • Author(s)
      Nishiwaki Hiroshi、Hamaguchi Tomonari、Ito Mikako、Ishida Tomohiro、Maeda Tetsuya、Kashihara Kenichi、Tsuboi Yoshio、Ueyama Jun、Shimamura Teppei、Mori Hiroshi、Kurokawa Ken、Katsuno Masahisa、Hirayama Masaaki、Ohno Kinji
    • Journal Title

      mSystems

      Volume: 5 Issue: 6

    • DOI

      10.1128/msystems.00797-20

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of Qk as a Glial Precursor Cell Marker that Governs the Fate Specification of Neural Stem Cells to a Glial Cell Lineage2020

    • Author(s)
      Takeuchi Akihide、Takahashi Yuji、Iida Kei、Hosokawa Motoyasu、Irie Koichiro、Ito Mikako、Brown J.B.、Ohno Kinji、Nakashima Kinichi、Hagiwara Masatoshi
    • Journal Title

      Stem Cell Reports

      Volume: 15 Issue: 4 Pages: 883-897

    • DOI

      10.1016/j.stemcr.2020.08.010

    • NAID

      120006888017

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Zonisamide ameliorates neuropathic pain partly by suppressing microglial activation in the spinal cord in a mouse model2020

    • Author(s)
      Koshimizu Hiroyuki、Ohkawara Bisei、Nakashima Hiroaki、Ota Kyotaro、Kanbara Shunsuke、Inoue Taro、Tomita Hiroyuki、Sayo Akira、Kiryu-Seo Sumiko、Konishi Hiroyuki、Ito Mikako、Masuda Akio、Ishiguro Naoki、Imagama Shiro、Kiyama Hiroshi、Ohno Kinji
    • Journal Title

      Life Sciences

      Volume: 263 Pages: 118577-118577

    • DOI

      10.1016/j.lfs.2020.118577

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibition of cyclooxygenase-1 by nonsteroidal anti-inflammatory drugs demethylates MeR2 enhancer and promotes Mbnl1 transcription in myogenic cells.2020

    • Author(s)
      Huang K, Masuda A, Chen G, Bushra S, Kamon M, Araki T, Kinoshita M, Ohkawara B, Ito M, Ohno K
    • Journal Title

      Sci Rep

      Volume: 10 Issue: 1 Pages: 2558-2558

    • DOI

      10.1038/s41598-020-59517-y

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ubiquitination of DNA Damage-Stalled RNAPII Promotes Transcription-Coupled Repair2020

    • Author(s)
      Nakazawa Y, Hara Y, Oka Y, Komine O, van den Heuvel D, Guo C, Daigaku Y, Isono M, He Y, Shimada M, Kato K, Jia N, Hashimoto S, Kotani Y, Miyoshi Y, Tanaka M, Sobue A, Mitsutake N, Suganami T, Masuda A, Ohno K, Nakada S, Mashimo T, Yamanaka K, Luijsterburg MS, Ogi T
    • Journal Title

      Cell

      Volume: 19 Issue: 6 Pages: 1228-1244

    • DOI

      10.1016/j.cell.2020.02.010

    • NAID

      120006871293

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Congenital myasthenic syndrome-associated agrin variants affect clustering of acetylcholine receptors in a domain-specific manner2020

    • Author(s)
      Ohkawara B, Shen X-M, Selcen D, Nazim M, Bril V, Tarnopolsky MA, Brady L, Fukami S, Amato AA, Yis U, Ohno K, Engel AG
    • Journal Title

      JCI Insight

      Volume: -

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Prediction of the splicing effects of SNVs affecting the first nucleotide G of an exon2021

    • Author(s)
      Joudaki1 A, Takeda J, Masuda A, Ohno K.
    • Organizer
      European Human Genetics Conference 2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Functional analysis of mutations in a glycosylation enzyme gene, GFPT1, underlying limb-girdle congenital myasthenic syndromes (CMS)2021

    • Author(s)
      Farshadyeganeh P, Ohkawara B, Kamon M, Araki T, Komaki H, Ohno K.
    • Organizer
      European Human Genetics Conference 2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The suppressive role for the splicing regulator, PTBP1, in the production of neuron-specific agrin isoform2021

    • Author(s)
      Bushra S, Lin Y, Joudaki A, Masuda A, Ohno K.
    • Organizer
      American Society of Human Genetics 2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 速筋の神経筋接合部終板における網羅的遺伝子発現解析2021

    • Author(s)
      伊藤美佳子、Kun Huang、大野欽司
    • Organizer
      第7回日本筋学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] InMeRF: A set of random forest models for each amino acid substitution to predict pathogenicity of missense variants in the human genome2020

    • Author(s)
      Takeda J, Nanatsue K, Yamagishi R, Ito M, Ohno K
    • Organizer
      European Society of Human Genetics Virtual Conference
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Effect of zonisamide on acetylcholine receptor cluster at the neuromuscular junction2020

    • Author(s)
      Inoue T, Ohkawara B, Nakashima H, Imagama S, Ishiguro N, Ohno K
    • Organizer
      ORS 2020 Annual Meeting (Poster), Phoenix, Arizona, USA
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Inhibition of cyclooxygenase-1 by nonsteroidal anti-inflammatory drugs demethylates MeR2 enhancer and promotes Mbnl1 transcription in myogenic cells2019

    • Author(s)
      Huang K, Masuda A, Ohkawara B, Ito M, Ohno K
    • Organizer
      5th Annual Meeting of Japan Muscle Society (Poster), Tokyo, Japan
    • Related Report
      2019 Research-status Report

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Published: 2019-07-04   Modified: 2023-05-23  

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