Elucidating the mechanism of abnormal protein aggregation in sporadic inclusion body myositis by single molecule nanoimaging

• Project/Area Number: 18K19505
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 52:General internal medicine and related fields
• Research Institution: Tohoku University
• Principal Investigator: Aoki Masashi 東北大学, 医学系研究科, 教授 (70302148)
• Co-Investigator(Kenkyū-buntansha): 割田 仁 東北大学, 大学病院, 助教 (30400245) ; 鈴木 直輝 東北大学, 医学系研究科, 非常勤講師 (70451599)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 封入体筋炎 / RNAシークエンス / 電気収縮培養 / TDP-43 / プロテアソーム / 骨格筋生物学 / 電気収縮 / 細胞内凝集体 / 筋収縮 / 筋芽細胞

Outline of Final Research Achievements

In this study, myoblasts were harvested from sporadic inclusion body myositis (sIBM) patients during muscle biopsy, and a total of six lines were stocked during these two years. Cellular stress was applied to human skeletal muscle using electro-pulse-constriction-culture-system (EPS) which reproduces long-lasting muscle contraction. Analysis was performed by RNA sequencing using cells before and after contraction stress. The characteristics of the co-culture system (EPS culture) were reported in an international journal. In addition, TDP-43, which is a component of the aggregates, is labeled by single-molecule nanoimaging, and the presence or absence of aggregate formation before and after EPS culture was evaluated. Furthermore, analysis of the myoblast specific proteasome deficient mouse revealed that p53 is important for the maintenance of myoblasts pool.

Academic Significance and Societal Importance of the Research Achievements

学術的には2報の論文を国際誌に掲載することができた。一つは封入体筋炎の病態に関与すると考えられる蛋白分解系であるプロテアソームの骨格筋における役割をStem Cell Reports誌に、もう一つは本研究課題の主要評価系である電気収縮培養のシステムとしての有用性についてSciRep誌に、それぞれ報告した。今後、本研究を発展させるうえで、いずれも重要な論文である。前者はプレスリリースも行い、社会的にも骨格筋生物学研究の意義について広く周知することができた。

Research Products

• [Journal Article] AMPK Complex Activation Promotes Sarcolemmal Repair in Dysferlinopathy (2020)
  • Author(s): Ono Hiroya、Suzuki Naoki、Kanno Shin-ichiro、Kawahara Genri、Izumi Rumiko、Takahashi Toshiaki、Kitajima Yasuo、Osana Shion、Nakamura Naoko、Akiyama Tetsuya、Ikeda Kensuke、Shijo Tomomi、Mitsuzawa Shio、Nagatomi Ryoichi、Araki Nobukazu、Yasui Akira、Warita Hitoshi、Hayashi Yukiko K.、Miyake Katsuya、Aoki Masashi
  • Journal Title: Molecular Therapy Volume: 28 Issue: 4 Pages: 1133-1153
  • DOI: 10.1016/j.ymthe.2020.02.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The updated retrospective questionnaire study of sporadic inclusion body myositis in Japan (2019)
  • Author(s): Suzuki Naoki、Mori-Yoshimura Madoka、Yamashita Satoshi、…Nishino Ichizo、Aoki Masashi
  • Journal Title: Orphanet Journal of Rare Diseases Volume: 14 Issue: 1 Pages: 155-163
  • DOI: 10.1186/s13023-019-1122-5
  • NAID: 120006956841
  • Peer Reviewed / Open Access
• [Journal Article] Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial (2019)
  • Author(s): Hanna Michael G、Badrising Umesh A、Benveniste Olivier、Lloyd Thomas E、Needham Merrilee、Chinoy Hector、Aoki Masashi、...Amato Anthony A
  • Journal Title: The Lancet Neurology Volume: 18 Issue: 9 Pages: 834-844
  • DOI: 10.1016/s1474-4422(19)30200-5
  • Peer Reviewed / Open Access
• [Journal Article] In vitro exercise model using contractile human and mouse hybrid myotubes (2019)
  • Author(s): Chen Weijian、Nyasha Mazvita R.、Koide Masashi、Tsuchiya Masahiro、Suzuki Naoki、Hagiwara Yoshihiro、Aoki Masashi、Kanzaki Makoto
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 11914-11914
  • DOI: 10.1038/s41598-019-48316-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Ubiquitin-Proteasome System Is Indispensable for the Maintenance of Muscle Stem Cells (2018)
  • Author(s): Kitajima Yasuo、Suzuki Naoki、Nunomiya Aki、Osana Shion、Yoshioka Kiyoshi、Tashiro Yoshitaka、Takahashi Ryosuke、Ono Yusuke、Aoki Masashi、Nagatomi Ryoichi
  • Journal Title: Stem Cell Reports Volume: 11 Issue: 6 Pages: 1523-1538
  • DOI: 10.1016/j.stemcr.2018.10.009
  • NAID: 120007006241
  • Peer Reviewed / Open Access / Int'l Joint Research