Mechanical control of energy metabolism in cardiomyocytes

• Project/Area Number: 24657127
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Cell biology
• Research Institution: Tohoku University
• Principal Investigator: OGURA Toshihiko 東北大学, 加齢医学研究所, 教授 (60273851)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 細胞力覚 / エネルギー代謝 / 心筋 / 力刺激 / エネルギー / 酸化的リン酸化

Research Abstract

Beating heart maintains constant circulation by responding to hemodynamics changes, such as altering blood pressure and heart rate. To adapt to high blood pressure, for example, cardiomyocytes must produce more ATP to contract even under the high mechanical overload. To explore a functional link between mechanical stimuli and energetic compensation, we searched for factors that respond to mechanical forces, and found a transcriptional co-activator that shuttles from cytoplasm to nucleus in response to physical force. This co-activator robustly activates nuclear receptors that regulate lipid metabolism in beating cardiomyocytes. As a result, this co-activator increases ATP production by enhancing oxidative phosphorylation (OxPhos) in mitochondria. Our finding provides an essential and novel insight on the energetic adaptation mechanism, in which drug targets can be found for therapy of heart diseases, such as heart failure.

Research Products

• [Journal Article] Gain-of-Function Mutations in RIT1 Cause Noonan Syndrome, a RAS/MAPK Pathway Syndrome (2013)
  • Author(s): Y. Aoki, T. Niihori, T. Banjo, N. Okamoto, S. Mizuno, K. Kurosawa, T. Ogata, F. Takada, M. Yano, T. Ando, T. Hoshika, C. Barnett, H. Ohashi, H. Kawame, T. Hasegawa, T. Okutani, T. Nagashima, S. Hasegawa, R. Funayama, T. Nagashima, K. Nakayama, S. Inoue, Y. Watanabe, T. Ogura, Y. Matsubara
  • Journal Title: The American Journal of Human Genetics Volume: 93 Pages: 173-180
  • Peer Reviewed
• [Journal Article] Haemodynamically dependent valvulogenesis of zebrafish heart is mediated by flow-dependent expression of miR-21 (2013)
  • Author(s): Banjo T, Grajcarek J, Yoshino D, Osada H, Miyasaka KY, Kida YS, Ueki Y, Nagayama K Kawakami K, Matsumoto T, Sato M, Ogura T
  • Journal Title: Nature Communications Volume: 4,1978 Issue: 1 Pages: 1978-1978
  • DOI: 10.1038/ncomms2978
  • Peer Reviewed / Open Access
• [Journal Article] Gain-of-Function Mutations in RIT1 Cause Noonan Syndrome, a RAS/MAPK Pathway Syndrome (2013)
  • Author(s): Aoki Y, Niihori T, Banio T, Okamoto N, Mizuno S, Kurosawa K, Ogata T, Takada F, Yano M, Ando T, Hoshika T, Barnett C, Ohashi H, Kawame H, Hasegawa T, Okutani T, Nagashima T, Hasegawa S, Funayama R, Nagashima T Nakayama K, Inoue S, Watanabe Y, Oeura T, Matsubara Y
  • Journal Title: The American Journal of Human Genetics Volume: Volume 93, Issue 1 Issue: 1 Pages: 173-180
  • DOI: 10.1016/j.ajhg.2013.05.021
  • Peer Reviewed
• [Journal Article] Fibroblast growth factor 10 gene regulation in the second heart field by Tbx1, Nkx2-5, and Islet1 reveals a genetic switch for down-regulation in the myocardium (2012)
  • Author(s): Y. Watanabe, S. Zaffran, A. Kuroiwa, H. Higuchi, T. Ogura, R. P. Harvey, R. G. Kelly, M. Buckingham.
  • Journal Title: Proc Natl Acad Sci USA Volume: 109 Pages: 18273-18280
  • Peer Reviewed
• [Journal Article] Roles of planar cell polarity signaling in maturation of neuronal precursor cells in the postnatal mouse olfactory bulb (2012)
  • Author(s): Y. Hirota, M. Sawada, Y. S. Kida, S. Huang, O. Yamada, M. Sakaguchi, T. Ogura, H. Okano, K. Sawamoto.
  • Journal Title: Stem Cells Volume: 30 Pages: 1726-1733
  • Peer Reviewed
• [Presentation] 生命現象を力学的に再解釈する、そして、生命現象を再構築する (2014)
  • Author(s): 小椋利彦
  • Organizer: 東京工業大学生体システム専攻バイオサイエンスシンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2014-02-18
  • Invited
• [Presentation] 生命現象を力を視点に再解釈するために (2013)
  • Author(s): 小椋利彦
  • Organizer: 生物物理学会東北支部
  • Place of Presentation: 仙台
  • Year and Date: 2013-12-13
  • Invited
• [Presentation] 細胞は力をどのように感知し、そのように反応するか (2013)
  • Author(s): 小椋利彦
  • Organizer: 日本人類遺伝学会大第8回大会特別講演
  • Place of Presentation: 仙台
  • Year and Date: 2013-11-21
  • Invited
• [Presentation] Physical forces as a regulator of morphogenesis and homeostasis (2013)
  • Author(s): 小椋利彦
  • Organizer: 第8回研究所ネットワーク国際シンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2013-06-27
• [Presentation] 力を視点に、生命現象を再解釈する (2013)
  • Author(s): 小椋利彦
  • Organizer: 第19回創発システムシンポジウム（創発夏の学校2013）チュートリアル講演＆ワークショップ
  • Place of Presentation: 大阪
  • Invited
• [Presentation] 生命現象を力を視点に再解釈する (2012)
  • Author(s): 小椋利彦
  • Organizer: 第19回創発システムシンポジウム(創発夏の学校2013)
  • Place of Presentation: 大阪
• [Presentation] 生命現象を力を視点に再解釈するために
  • Author(s): 小椋利彦
  • Organizer: 生物物理学会東北支部会
  • Place of Presentation: 仙台
  • Invited
• [Presentation] 細胞は力をどのように感知し、どのように反応するか
  • Author(s): 小椋利彦
  • Organizer: 日本人類遺伝学会大８回大会特別講演
  • Place of Presentation: 仙台
  • Invited
• [Presentation] Physical forces as a regulator of morphogenesis and homeostasis – paving a way to medical application
  • Author(s): 小椋利彦
  • Organizer: 第8回研究所ネットワーク国際シンポジウム
  • Place of Presentation: 京都
  • Invited