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A study of mitochondrial function on the mechanisms of heartbeat initiation in embryonic heart

Research Project

Project/Area Number 19K07286
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 48020:Physiology-related
Research InstitutionSapporo Medical University

Principal Investigator

Noritsugu Tohse  札幌医科大学, 医学部, 教授 (80192657)

Co-Investigator(Kenkyū-buntansha) 佐藤 達也  札幌医科大学, 医学部, 助教 (40592473)
一瀬 信敏  札幌医科大学, 医学部, 助教 (60448610)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2020: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000)
Fiscal Year 2019: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Keywords胎児心臓 / 心臓代謝 / ミトコンドリア機能 / サルコメア構造 / 胎児循環 / 興奮収縮連関 / 筋原線維 / 心筋 / 発生期 / エネルギー代謝 / ミトコンドリア / 心拍動
Outline of Research at the Start

心拍動開始前後の胎児心筋のエネルギー代謝の詳細を特にミトコンドリア 機能に着目し、心拍動維持と興奮収縮連関との関連性について明らかにする。ラットの胎児を用い、遺伝子発現の確認、中間代謝産物の網羅的な評価、酸素消費速度と細胞外酸性化速度の解析、ミトコンドリア複合体の複合体構造の解析、蛋白発現定量、活性酸素種の産生量の定量、走査型電子顕微鏡による心筋ミトコンドリアの形態と分布の評価などを行い心臓拍動開始時のエネルギー代謝を制御する鍵となる分子を同定する。また、心拍動開始直前の心臓原基で解糖系やミトコンドリア呼吸鎖とカルシウムトランジェント、電気活動、および心拍動との関連を解明する。

Outline of Final Research Achievements

The initiation of heartbeat is an essential step in cardiogenesis in the heart primordium, but it remains unclear how intracellular metabolism responds to increased energy demands after heartbeat initiation. Myofibrillogenesis is an essential process for cardiogenesis and is closely related to excitation-contraction coupling and the maintenance of heartbeat. However, how myofibrils and sarcomeres are associated with heartbeat initiation in the early embryonic heart development also remains unclear. In our study, it is suggested that the HIF-1α-mediated enhancement of glycolysis with activation of the pentose phosphate pathway, potentially leading to antioxidant defense and nucleotide biosynthesis, covers the increased energy demand in the beating heart. And it is also suggested that heartbeat initiation can be induced by development of bundles of myofilaments with up-regulated proteins associated with myofibrillogensis, whereas sarcomeres are not required for the initial heartbeat.

Academic Significance and Societal Importance of the Research Achievements

本研究は、生命の源と言える心拍動開始のメカニズムを、実際の心筋細胞を用い、エネルギー代謝の観点から明らかにするものであり、心臓拍動開始前後といった、心筋細胞への分化が決定される重要な時期に、実際の心臓における心臓拍動維持に必要な機構を解明することで再生医療の発展にも寄与できる。また、低酸素環境下でも自動能を維持する心筋細胞の仕組みが分かれば、洞不全症候群など疾患の新しい治療法の開発にも繋がる可能性がある。以上より、本研究は今後臨床応用が期待されている再生医療に実際の心臓の生理学的知見の提供という貢献を行うことができ、独自性・独創性が高く研究価値が高いと考える。

Report

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

    (9 results)

All 2022 2021 2020 2019

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (7 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Enhanced glucose metabolism through activation of HIF-1α covers the energy demand in a rat embryonic heart primordium after heartbeat initiation2022

    • Author(s)
      Sato Tatsuya、Ichise Nobutoshi、Kobayashi Takeshi、Fusagawa Hiroyori、Yamazaki Hiroya、Kudo Taiki、Tohse Noritsugu
    • Journal Title

      Scientific Reports

      Volume: 12 Issue: 1

    • DOI

      10.1038/s41598-021-03832-5

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ultrastructural Assessment and Proteomic Analysis in Myofibrillogenesis in the Heart Primordium after Heartbeat Initiation in Rats.2022

    • Author(s)
      Nobutoshi Ichise, Tatsuya Sato, Hiroyori Fusagawa, Hiroya Yamazaki, Taiki Kudo, Izaya Ogon and Noritsugu Tohse
    • Journal Title

      Frontiers in Physiology

      Volume: -

    • DOI

      10.3389/fphys.2022.907924

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Intracellular glucose metabolism is enhanced with activation of hypoxia-inducible factor-1α (HIF-1α) in a rat embryonic heart primordium after heartbeat initiation.2022

    • Author(s)
      Tatsuya Sato, Nobutoshi Ichise, Hiroyori Fusagawa, Hiroya Yamazaki, Taiki Kudo, Izaya Ogon, Noritsugu Tohse.
    • Organizer
      第99回日本生理学会大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Characteristics of sarcomere formation and expression patterns of myofibrillar components in a rat embryonic heart primordium after heartbeat initiation.2022

    • Author(s)
      Hiroya Yamazaki, Nobutoshi Ichise, Tatsuya Sato, Taiki Kudo, Hiroyori Fusagawa, Izaya Ogon, Noritsugu Tohse.
    • Organizer
      第99回日本生理学会大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 心拍動開始後のラット胎児心臓原基では低酸素誘導因子1α (HIF-1α) の発現増加を伴い 細胞内糖代謝が変化する2021

    • Author(s)
      佐藤 達也,一瀬 信敏, 房川 祐頼, 山﨑寛也, 工藤 大樹, 黄金 勲矢, 當瀬 規嗣
    • Organizer
      第101回日本生理学会地方会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 心拍動開始時の胎児ラット心臓原基におけるCa2+ハンドリングに関わる分子発現変化の特徴2020

    • Author(s)
      房川祐頼、佐藤達也、一瀬信敏、小林武志、山﨑寛也、寺島嘉紀、當瀬規嗣
    • Organizer
      第100回日本生理学会北海道地方会
    • Related Report
      2020 Research-status Report
  • [Presentation] Energy metabolism in rat fetal hearts just after the initiation of heartbeat is altered via increased glycolytic flux and activated mitochondrial function.2020

    • Author(s)
      Tatsuya Sato, Nobutoshi Ichise, Takeshi Kobayashi, Hiroya Yamazaki, Yoshinori Terashima, Noritsugu Tohse
    • Organizer
      64th Annual Meeting of the Biophysical Society
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Mitochondrial aerobic respiration in the fetal heart is activated just after initiation of the heartbeat.2020

    • Author(s)
      Tatsuya Sato, Nobutoshi Ichise, Takeshi Kobayashi, Hiroya Yamazaki, Yoshinori Terashima, Noritsugu Tohse
    • Organizer
      第97回日本生理学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] ラット胎生心の心拍動開始時におけるミトコンドリア機能の検討2019

    • Author(s)
      佐藤達也、一瀬信敏、山﨑寛也、小林武志、寺島嘉紀、千葉充将、當瀬規嗣
    • Organizer
      第99回日本生理学会北海道地方会
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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