Functional analysis of non-proteolytic calpain to the skeletal muscle development via RhoA activity

• Project/Area Number: 15K21367
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General anatomy (including histology/embryology); General medical chemistry
• Research Institution: The University of Tokyo
• Principal Investigator: Tonami Kazuo 東京大学, 大学院医学系研究科(医学部), 助教 (70511393)
• Research Collaborator: MIYAZAKI Takuro 昭和大学, 医学部, 講師 (80398693)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: カルパイン / 低分子量Gタンパク質 / 筋分化 / 骨格筋 / 細胞骨格 / アクチン / 動脈硬化

Outline of Final Research Achievements

CAPN6 is a suppressor of skeletal muscle differentiation. In this study we elucidated the regulation of RhoA activity by CAPN6 is important as the molecular mechanism under skeletal muscle development. As a molecular mechanism of CAPN6 regulating RhoA activity, it is suggested that CAPN5 which has highest similarity to CAPN6 in the protein structure could regulate the activity of small G-protein. This result led us to focus to CAPN5 as counterpart of CAPN6 in the regulation of small G protein. In the aspect of pathological function of CAPN6, we found that macrophage CAPN6 exacerbates atherosclerotic diseases via suppressing pinocytosis of LDL. In this process the suppression of Rac1 expression by CAPN6 and CWC22 association plays a significant role. In this study we found physiological and pathological significant of the CAPN6 cellular function of regulating small G protein.

Research Products

• [Int'l Joint Research] エディンバラ大学(英国)
• [Int'l Joint Research] ゲオルク・アウグスト大学ゲッティンゲン(ドイツ)
• [Int'l Joint Research] University of Edinburgh(英国)
• [Int'l Joint Research] UNIVERSITY MEDICAL CENTER GOETTINGEN(ドイツ)
• [Journal Article] Calpain-6 confers atherogenicity to macrophages by dysregulating pre-mRNA splicing. (2016)
  • Author(s): Miyazaki T, Tonami K, Hata S, Aiuchi T, Ohnishi K, Lei XF, Kim-Kaneyama JR, Takeya M, Itabe H, Sorimachi H, Kurihara H, Miyazaki A
  • Journal Title: J Clin Invest Volume: 126 Issue: 9 Pages: 3417-3432
  • DOI: 10.1172/jci85880
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 細胞の協調動態の観察とモデリング (2017)
  • Author(s): 礪波 一夫, 金井 政宏, 戸澤 英人, 牛島 俊征, 田久保 直子, 内島 泰信, 時弘 哲治, 栗原 裕基
  • Organizer: 生命動態合同シンポジウム2017
  • Place of Presentation: 理化学研究所 生命システム研究センター（大阪府吹田市）
  • Year and Date: 2017-03-17
• [Presentation] Disturbance of pre-mRNA splicing by calpain-6 aggravates macrophage cholesterol deposition in atherosclerotic lesions (2016)
  • Author(s): Takuro Miyazaki, Kazuo Tonami, Shoji Hata, Toshihiro Aiuchi, Koji Ohnishi, Xiao-Feng Lei, Joo-ri Kim-Kaneyama, Motohiro Takeya, Hiroyuki Itabe, Hiroyuki Sorimachi, Hiroki Kurihara and Akira Miyazaki
  • Organizer: 第２４回血管生物医学会学術集会
  • Place of Presentation: 長崎ブリックホール（長崎県長崎市）
  • Year and Date: 2016-12-09
• [Presentation] Calpain-6 potentiates pro-atherogenic pinocytosis in macrophages (2016)
  • Author(s): Takuro Miyazaki, Kazuo Tonami, Shoji Hata, Toshihiro Aiuchi, Koji Ohnishi, Xiao-Feng Lei, Joo-ri Kim-Kaneyama, Motohiro Takeya, Hiroyuki Itabe, Hiroyuki Sorimachi, Hiroki Kurihara and Akira Miyazaki
  • Organizer: 19th International Vascular Biology Meeting
  • Place of Presentation: ボストン（U.S.A）
  • Year and Date: 2016-11-01
  • Int'l Joint Research