Elucidation of the mechanism in which mechanostress modulates cardiac microtubules dynamics

• Project/Area Number: 18K08105
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: National Cardiovascular Center Research Institute (2019-2020); Osaka University (2018)
• Principal Investigator: SHINTANI YASUNORI 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (20712243)
• Co-Investigator(Kenkyū-buntansha): 塚本 蔵 大阪大学, 生命機能研究科, 准教授 (80589151)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: AMPK / 介在板 / メカノストレス / 心臓介在板 / 微小管

Outline of Final Research Achievements

In this study, we identified an active form of AMP-activated protein kinase (AMPK) localized at the intercalated disks in the heart, a specific cell–cell junction present between cardiomyocytes. A contractile inhibitor, MYK-461, prevented the localization of AMPK at the intercalated disks, suggesting that the localization of AMPK is regulated by mechanical stress. MYK-461 increased the individual cell area of cardiomyocytes in CLIP-170 phosphorylation-dependent manner. Moreover, heart-specific CLIP-170 S311A transgenic mice demonstrated elongation of cardiomyocytes along with accumulated microtubules (MTs), leading to progressive decline in cardiac contraction. In conclusion, AMPK regulates the cell shape and aspect ratio of cardiomyocytes by modulating the turnover of MTs through homeostatic phosphorylation of CLIP-170 at the intercalated disks.

Academic Significance and Societal Importance of the Research Achievements

介在板を発信源とするAMPKメカノシグナルによる心筋微小管の動的制御機構を明らかにし、その基質としてCLIPリン酸化が心疾患の病態形成に関わる可能性を示した。

Research Products

• [Journal Article] The CR9 element is a novel mechanical load‐responsive enhancer that regulates natriuretic peptide genes expression (2021)
  • Author(s): Miyashita Y, Tsukamoto O, Matsuoka K, Kamikubo K, Kuramoto Y, Fu HY, Tsubota T, Hasuike H, Takayama T, Ito H, Hitsumoto T, Okamoto C, Kioka H, Oya R, Shinomiya H, Hakui H, Shintani Y, Kato H, Kitakaze M, Sakata Y, Asano Y, Takashima S
  • Journal Title: The FASEB Journal Volume: 35 Issue: 4
  • DOI: 10.1096/fj.202002111rr
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] AMPK regulates cell shape of cardiomyocytes by modulating turnover of microtubules through CLIP‐170 (2020)
  • Author(s): Yashirogi Shohei、Nagao Takemasa、Nishida Yuya、Takahashi Yusuke、Qaqorh Tasneem、Yazawa Issei、Katayama Toru、Kioka Hidetaka、Matsui Tsubasa S、Saito Shigeyoshi、Masumura Yuki、Tsukamoto Osamu、Kato Hisakazu、Ueda Hiromichi、Yamaguchi Osamu、Yashiro Kenta、Yamazaki Satoru、Takashima Seiji、Shintani Yasunori
  • Journal Title: EMBO reports Volume: 22 Issue: 1
  • DOI: 10.15252/embr.202050949
  • Peer Reviewed / Open Access
• [Journal Article] In vivo real‐time ATP imaging in zebrafish hearts reveals G0s2 induces ischemic tolerance (2020)
  • Author(s): Kioka Hidetaka、Kato Hisakazu、Fujita Takeshi、Asano Yoshihiro、Shintani Yasunori、Yamazaki Satoru、Tsukamoto Osamu、Imamura Hiromi、Kogo Mikihiko、Kitakaze Masafumi、Sakata Yasushi、Takashima Seiji
  • Journal Title: The FASEB Journal Volume: 34 Issue: 2 Pages: 2041-2054
  • DOI: 10.1096/fj.201901686r
  • Peer Reviewed
• [Journal Article] Higd1a improves respiratory function in the models of mitochondrial disorder (2019)
  • Author(s): Nagao Takemasa、Shintani Yasunori、Hayashi Takaharu、Kioka Hidetaka、Kato Hisakazu、Nishida Yuya、Yamazaki Satoru、Tsukamoto Osamu、Yashirogi Shohei、Yazawa Issei、Asano Yoshihiro、Shinzawa‐Itoh Kyoko、Imamura Hiromi、Suzuki Takeo、Suzuki Tsutomu、Goto Yu‐ichi、Takashima Seiji
  • Journal Title: The FASEB Journal Volume: 34 Issue: 1 Pages: 1859-1871
  • DOI: 10.1096/fj.201800389r
  • Peer Reviewed
• [Journal Article] Endocardium differentiation through Sox17 expression in endocardium precursor cells regulates heart development in mice (2019)
  • Author(s): Saba Rie、Kitajima Keiko、Rainbow Lucille、Engert Silvia、Uemura Mami、Ishida Hidekazu、Kokkinopoulos Ioannis、Shintani Yasunori、Miyagawa Shigeru、Kanai Yoshiakira、Kanai-Azuma Masami、Koopman Peter、Meno Chikara、Kenny John、Lickert Heiko、Saga Yumiko、Suzuki Ken、Sawa Yoshiki、Yashiro Kenta
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 11953-11953
  • DOI: 10.1038/s41598-019-48321-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A molecular triage process mediated by RING finger protein 126 and BCL2-associated athanogene 6 regulates degradation of G0/G1 switch gene 2 (2019)
  • Author(s): Kamikubo Kenta、Kato Hisakazu、Kioka Hidetaka、Yamazaki Satoru、Tsukamoto Osamu、Nishida Yuya、Asano Yoshihiro、Imamura Hiromi、Kawahara Hiroyuki、Shintani Yasunori、Takashima Seiji
  • Journal Title: Journal of Biological Chemistry Volume: 294 Issue: 40 Pages: 14562-14573
  • DOI: 10.1074/jbc.ra119.008544
  • Peer Reviewed