Involvement of Synoviolin in Muscle metabolism via two distinct pathways

• Project/Area Number: 16H05157
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Tokyo Medical University
• Principal Investigator: Nakajima Toshihiro 東京医科大学, 医学部, 教授 (90260752)
• Co-Investigator(Kenkyū-buntansha): 八木下 尚子 聖マリアンナ医科大学, 医学研究科, 講師 (40367389) ; 荒谷 聡子 東京医科大学, 医学部, 講師 (40387064) ; 藤田 英俊 東京医科大学, 医学部, 講師 (90571802)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2018: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2017: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2016: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
• Keywords: サルコペニア / 遺伝子改変動物 / タンパク質分解 / シノビオリン / ユビキチン化

Outline of Final Research Achievements

We have been studying the role of synoviolin in several energy metabolism organs including white adipose tissue and liver. In this study, we focused on the role of synoviolin in skeletal muscle which is one of the representative energy metabolizing organs. The muscle-specific synoviolin knockout mice showed the severe muscle atrophy at 6 weeks of birth. In addition, pathological and physiological analyses demonstrated that the muscle atrophy mainly occurred in fast muscle fibers and muscle strength was also reduced.
These results reinforce our previous finding that synoviolin plays a pivotal key regulator of energy metabolism. Taken together, this study could provide the new model to investigate muscle atrophy including sarcopenia.

Academic Significance and Societal Importance of the Research Achievements

超高齢化社会を迎えた日本では運動器の障害により日常生活に支援や介護が必要となる方が増加している。平均余命が延びている分だけ、運動器の健康を長く保つ必要があり、サルコペニアの病態研究は国民にとって喫緊の最重要課題の一つである（「健康日本21」より）。しかし、「加齢」という生命現象自体が未だ謎の点が多く、期間、その他の要因など問題がある。本研究によりこれらを解決した迅速に得られる新規筋萎縮モデルを提供でき、本分野の研究の発展に寄与できよう。

Research Products

• [Journal Article] RADDAR-J Research and Developmental Group National platform for Rare Diseases Data Registry of Japan (2019)
  • Author(s): Furusawa Y, Yamaguchi I, Yagishita N, Tanzawa K, Matsuda F, Yamano Y.
  • Journal Title: Learning Health Systems Volume: －
  • Peer Reviewed / Open Access
• [Journal Article] The NRF2-PGC-1β pathway activates kynurenine aminotransferase 4 via attenuation of an E3 ubiquitin ligase, Synoviolin, in a cecal ligation/perforation -induced septic mouse model. (2018)
  • Author(s): Ishida Y, Fujita H, Aratani S, Chijiiwa M, Taniguchi N, Yokota M, Ogihara Y, Uoshima N, Nagashima F, Uchino H, Nakajima T.
  • Journal Title: Mol. Med. Rep. Volume: 18(2) Pages: 2467-2475
  • Peer Reviewed / Open Access
• [Journal Article] What occurs in human papilloma virus vaccination-associated neuro-immunopathic syndrome (HANS)? : implications of previous animal model studies (2018)
  • Author(s): Aratani S, Kuroiwa Y, Fujita H, Usui C, Yokota S, Nakamura I, Nishioka K, Nakajima T
  • Journal Title: The Autonomic Nervous System (自律神経 @日本自律 神経学会) Volume: 55(3) Pages: 165-170
  • Peer Reviewed
• [Journal Article] An E3 Ubiquitin Ligase, Synoviolin, Is Involved in the Degradation of Homocysteine-Inducible Endoplasmic Reticulum Protein. (2018)
  • Author(s): Maeda T, Fujita Y, Tanabe-Fujimura C, Zou K, Liu J, Liu S, Kikuchi K, Shen X, Nakajima T, Komano H.
  • Journal Title: Biol. Pharm. Bull. Volume: 41(6) Pages: 915-919
  • NAID: 130007382735
  • Peer Reviewed / Open Access
• [Journal Article] Identification of the inhibitory activity of E3 ligase Syvn1 in walnut extract. (2018)
  • Author(s): Fujita H, Aratani S, Yagishita N, Nishioka K, Nakajima T.
  • Journal Title: Mol. Med. Rep. Volume: 8(6) Pages: 5701-5708
  • Peer Reviewed / Open Access
• [Journal Article] Abatacept in combination with methotrexate in Japanese biologic-naive patients with active rheumatoidarthritis: a randomised placebocontrolledphase IV study. (2018)
  • Author(s): Matsubara T, Inoue H,Nakajima T, Tanimura K, Sagawa A, Sato Y, Osano K, Nagano S, Ueki Y, Hanyu T, Hashizume K, Amano N, Tanaka Y, Takeuchi T.
  • Journal Title: RMD Open. Volume: 4;4(2)
  • Peer Reviewed / Open Access
• [Journal Article] 線維筋痛症の病態・病因 (2018)
  • Author(s): 荒谷 聡子、中島 利博
  • Journal Title: 日本臨牀 Volume: 76 (11) Pages: 1921-1926
• [Journal Article] Mogamulizumab (Anti-CCR4) in HTLV-1-Associated Myelopathy. (2018)
  • Author(s): Sato T, Coler-Reilly ALG, Yagishita N, Araya N, Inoue E, Furuta R, Watanabe T, Uchimaru K, Matsuoka M, Matsumoto N, Hasegawa Y, Yamano Y.
  • Journal Title: N Engl J Med. Volume: 378(6) Issue: 6 Pages: 529-538
  • DOI: 10.1056/nejmoa1704827
  • Peer Reviewed / Open Access
• [Journal Article] Proposal of Classification Criteria for HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis Disease Activity. (2018)
  • Author(s): Sato T, Yagishita N, Tamaki K, Inoue E, Hasegawa D, Nagasaka M, Suzuki H, Araya N, Ariella Coler-Reilly, Hasegawa Y, Tsuboi Y, Takata A, Yamano Y.
  • Journal Title: Front Microbiol Volume: 25(9) Pages: 1651-1651
  • DOI: 10.3389/fmicb.2018.01651
  • Peer Reviewed / Open Access
• [Journal Article] Human papilloma virus vaccination (HPVV)-associated neuro-immunopathic syndrome (HANS): a comparative study of the symptomatic complex occurring in Japanese and Danish young females after HPVV (2018)
  • Author(s): Kuroiwa Y, Yokota S, Nakamura I, Nakajima T, Nishioka K
  • Journal Title: The Autonomic Nervous System (自律神経 @日本自律） Volume: 55(1) Pages: 21-30
• [Journal Article] Rheumatic heart disease in Central Asia (2018)
  • Author(s): Nakajima T
  • Journal Title: Translating Reserch To Impact Volume: 3 Pages: 27-29
• [Journal Article] 「アレルギーの臨床」に寄せる-885-「関節リウマチ発症因子シノビオリン」 (2017)
  • Author(s): 八木下尚子、中島利博
  • Journal Title: アレルギーの臨床 Volume: 37(9) Pages: 72-78
• [Journal Article] ヒト・パピローマ・ウィルスワクチン接種後の多彩な神経症候に関する病態考察 視床下部L1プロテイノパチー仮説 (2017)
  • Author(s): 黒岩義之、横田 俊平、平井 利明, 中島 利博, 中村 郁朗, 西岡 久寿樹
  • Journal Title: 自律神経 Volume: 54(2) Pages: 96-108
• [Journal Article] Effectiveness of Daily Prednisolone to Slow Progression of HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis: A Multi-Center Retrospective Cohort Study. (2017)
  • Author(s): Coler-Reilly ALG, Sato T, Matsuzaki T, Nakagawa M, Niino M, Nagai M, Nakamura T, Takenouchi N, Araya N, Yagishita N, Inoue E, Yamano Y.
  • Journal Title: Neurotherapeutics Volume: 14(4) Issue: 4 Pages: 1084-1094
  • DOI: 10.1007/s13311-017-0533-z
  • Peer Reviewed / Open Access
• [Journal Article] Inhibitory effects of ubiquitination of synoviolin by PADI4. (2017)
  • Author(s): Aratani S, Fujita H, Yagishita N, Yamano Y, Okubo Y, Nishioka K, Nakajima T
  • Journal Title: Mol. Med. Rep Volume: in press
  • Peer Reviewed
• [Journal Article] A Study of Brain Metabolism in Fibromyalgia by Positron Emission Tomography (2017)
  • Author(s): Usui C, Soma T, Hatta K, Aratani S, Fujita H, Nishioka K, Machida Y, Kuroiwa Y, Nakajima T, Nishioka K
  • Journal Title: Prog Neuropsychopharmacol Biol Psychiatry. Volume: 75 Pages: 120-127
  • DOI: 10.1016/j.pnpbp.2017.01.012
  • Peer Reviewed / Open Access
• [Journal Article] Murine hypothalamic destruction with vascular cell apoptosis subsequent to combined administration of human papilloma virus vaccine and pertussis toxin (2016)
  • Author(s): Aratani S, Fujita H, Kuroiwa Y, Usui C, Yokota S, Nakamura I, Nishioka K, Nakajima T
  • Journal Title: Sci.Rep Volume: 6 Issue: 1 Pages: 36943-36943
  • DOI: 10.1038/srep36943
  • Peer Reviewed / Open Access
• [Journal Article] Notch2 signaling regulates the proliferation of murine bone marrow-derived mesenchymal stem/stromal cells via c-Myc expression. (2016)
  • Author(s): Yukio S, Mabuchi Y, Miyamoto K, Araki D, Niibe K, Houlihan DD, Morikawa S, Nakagawa T, Nakajima T, Akazawa C, Hori S, Okano H, Matsuzaki Y
  • Journal Title: PLOS ONE Volume: 11（11） Issue: 11 Pages: 0165946-0165946
  • DOI: 10.1371/journal.pone.0165946
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A case of fibromyalgia involving pain throughout the body treated with site-specific targeted pain control. (2016)
  • Author(s): Nakajima F, Aratani S, Fujita H, Nakatani K, Makita K, Nakajima T
  • Journal Title: Springerplus Volume: 5 Issue: 1 Pages: 1027-1027
  • DOI: 10.1186/s40064-016-2572-z
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial Ubiquitin Ligase Activator of NF-κB (MULAN) regulates NF-κB signaling in ER stress-stimulated cells. (2016)
  • Author(s): Fujita H, Aratani S, Fujii R, Yamano Y, Yagishita N, Araya N, Izumi T, Azakami K, Hasegawa D, Nishioka K and Nakajima T
  • Journal Title: Int J Mol Med. Volume: 37 Issue: 6 Pages: 1611-1618
  • DOI: 10.3892/ijmm.2016.2566
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] NAD(P)H quinone oxidoreductase 1 inhibits the proteasomal degradation of homocysteine-inducible endoplasmic reticulum protein. (2016)
  • Author(s): Maeda T, Tanabe-Fujimura C, Fujita Y, Abe C, Nanakida Y, Kun Zou, Liu J, Liu S, Nakajima T, Komano H
  • Journal Title: Biochem Biophys Res Commun Volume: 473（4） Pages: 1276-1280
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Adverse effects of human papolloma virus vaccination on central nervous system:Neuro-endocrinological disorders of hypothalamo-pituitary axis. (2016)
  • Author(s): Hirai T,Kuroiwa Y,Hayashi T,Uchiyama M,Nakamura I,Yokota S, Nakajima T, Iguchi Y
  • Journal Title: The Autonomic Nervous System Volume: 53（1） Pages: 49-64
  • Peer Reviewed
• [Presentation] What Rheumatoid synovial cells tell us: apoptosis. (2018)
  • Author(s): Nakajima T
  • Organizer: APLAR’S EXTENSIVE COURSE ON RHEUMATOLOGY
  • Int'l Joint Research / Invited
• [Presentation] 脳内炎症に関わるキヌレニンの代謝機構の解明 (2018)
  • Author(s): 藤田 英俊、石田 裕介、荒谷 聡子、横田 真穂、内野 博之、中島 利博
  • Organizer: 日本線維筋痛症学会第 10 回学術集会
• [Presentation] 線維筋痛症の栄養状態と痛み関連障害について (2018)
  • Author(s): 薦田 昭宏、橋本 聡子、河野 麻衣、手島 議起、澤田 純、中谷 孝、中島 利博
  • Organizer: 日本線維筋痛症学会第 10 回学術集会
• [Presentation] だいいちリハビリテーション病院における精神科診療－精神科医の役割は (2018)
  • Author(s): 石川 洋世、北川 中行、中谷 孝、中島 利博
  • Organizer: 日本線維筋痛症学会第 10 回学術集会
• [Presentation] 線維筋痛症における当院での関節超音波検査の取り組み (2018)
  • Author(s): 西森 美佐子、中平 律子、山口 結花、梅原由加里、荒谷 聡子、中島 若巳、北川 中行、中谷 孝、中島 利博
  • Organizer: 日本線維筋痛症学会第 10 回学術集会
• [Presentation] HPVワクチン関連神経免疫異常症候群（HANS）におけるoutbreak peakに関する検討 (2017)
  • Author(s): 大西孝宏、横田俊平、中島利博、西岡久寿樹
  • Organizer: 第 61 回日本リウマチ学会 総会・学術集会
• [Presentation] SPACI1/SAAL1が制御する CKD6 発現量の減少は RA 滑膜細胞の増殖を制御する (2017)
  • Author(s): 小松梨恵、遊道和雄、仁木久照、西岡久寿樹、中島利博、藤井亮爾
  • Organizer: 第 61 回日本リウマチ学会 総会・学術集会
• [Presentation] ユビキチン化酵素シノビオリンの発見から臨床応用 (2017)
  • Author(s): 中島利博
  • Organizer: 第 13 回日本臨床プロテオーム研究会
• [Presentation] A study on our novel murine model of Humanpapillomavirus-associated Neuroimmunopathic Syndrome (HANS) (2017)
  • Author(s): Nakajima T, Aratani S, Fujita H, Kuroiwa Y, Usui C, Yokota S, Nakamura I, Nishioka K
  • Organizer: 国際自律神経学会 ISAN2017
  • Int'l Joint Research
• [Presentation] Synoviolin as a novel factor for Rhematoid Arthritis, chronic inflammation and metabolic disorders (2017)
  • Author(s): Nakajima T
  • Organizer: 18th Myanmar Internal Medicine Conference 2017(in conjunction with 4th AFIM congress and 4th ACP Southeast Asian Chapter Meeting)
  • Int'l Joint Research
• [Presentation] モデルマウスを用いたヒトパピローマウイルスワクチン関連神経免疫異常症候群の病態解析 (2017)
  • Author(s): 荒谷聡子、藤田英俊、黒岩義之、臼井千恵、横田俊平、中村郁郎、西岡久寿樹、中島利博
  • Organizer: 日本線維筋痛症学会 第 9 回学術集会
• [Presentation] 線維筋痛症における関節超音波検査の活用法 (2017)
  • Author(s): 西森美佐子、中平律子、山口結花、梅原由加里、荒谷聡子、中島若巳、北川中行、中谷孝、中島利博
  • Organizer: 日本線維筋痛症学会 第 9 回学術集会
• [Presentation] 当院における線維筋痛症の短期入院の痛み関連障害について (2017)
  • Author(s): 薦田昭宏、橋本聡子、手島郁恵、河野麻衣、渡邉彩花、中島若巳、中谷孝、中島利博
  • Organizer: 日本線維筋痛症学会 第 9 回学術集会
• [Presentation] Development of novel regulatory methods of mitochondrial functions (2017)
  • Author(s): Fujita H, Aratani S, Yokota M and Nakajima T
  • Organizer: The 16th International Symposium on Advanced Technology (ISAT-16)
  • Int'l Joint Research
• [Presentation] HTLV-1関連脊髄症（HAM）の新たな運動障害重症度評価指標の提案 (2017)
  • Author(s): 八木下尚子、佐藤知雄、長谷川大輔、新谷奈津美、井上永介、高田礼子、山野嘉久
  • Organizer: 日本HTLV-1学会
• [Presentation] 関節リウマチにおける転写後修飾による多重化シグナル調節機構の解析。 (2016)
  • Author(s): 荒谷聡子、藤田英俊、八木下尚子、山野嘉久、西岡久寿樹、中島利博
  • Organizer: 第 3 回 JCR ベーシックリサーチカンファレンス
  • Place of Presentation: アキバホール（東京 千代田区）
  • Year and Date: 2016-10-14
• [Presentation] リウマチ発症因子シノビオリンによる新規エネルギー代謝機構の解明。 (2016)
  • Author(s): 藤田英俊、荒谷聡子、八木下尚子、山野嘉久、須藤カツ子、内野博之、西岡久寿樹、中島利博
  • Organizer: 第 3 回 JCR ベーシックリサーチカンファレンス
  • Place of Presentation: アキバホール（東京 千代田区）
  • Year and Date: 2016-10-14
• [Presentation] シノビオリンが拓く慢性炎症・関節リウマチの病態メカニズムと新規治療法の開発。 (2016)
  • Author(s): 中島利博
  • Organizer: 第 31 回日本整形外科学会基礎学術集会
  • Place of Presentation: 福岡国際会議場(福岡県 福岡市)
  • Year and Date: 2016-10-13
• [Presentation] シノビオリン阻害剤の探索。 (2016)
  • Author(s): 藤田英俊、荒谷聡子、西岡久寿樹、中島利博
  • Organizer: 日本線維筋痛症学会第 8 回学術集会
  • Place of Presentation: KFC Hall & Rooms（東京 墨田区）
  • Year and Date: 2016-09-17
• [Presentation] マウスモデルを用いたシノビオリン阻害活性を有する天然物の効果の検証。 (2016)
  • Author(s): 藤田英俊、荒谷聡子、西岡久寿樹、中島利博
  • Organizer: 日本線維筋痛症学会第 8 回学術集会
  • Place of Presentation: KFC Hall & Rooms（東京 墨田区）
  • Year and Date: 2016-09-17
• [Presentation] ヒトにおけるシノビオリン阻害剤の効果の検証。 (2016)
  • Author(s): 藤田英俊、荒谷聡子、西岡久寿樹、中島利博
  • Organizer: 日本線維筋痛症学会第 8 回学術集会
  • Place of Presentation: KFC Hall & Rooms（東京 墨田区）
  • Year and Date: 2016-09-17
• [Presentation] 新規自己炎症症候群モデルマウスの樹立とシノビオリン阻害剤の効果。 (2016)
  • Author(s): 中島利博
  • Organizer: 第 17 回 運動器科学研究会
  • Place of Presentation: 大阪大学中之島センター(大阪府 大阪市)
  • Year and Date: 2016-09-02
• [Presentation] リウマチ発症因子シノビオリンによるエネルギー代謝調節の解明。 (2016)
  • Author(s): 藤田英俊
  • Organizer: 第17 回 運動器科学研究会
  • Place of Presentation: 大阪大学中之島センター（大阪府 大阪市）
  • Year and Date: 2016-09-02
• [Presentation] シノビオリン阻害剤の実用化に向けて。 (2016)
  • Author(s): 荒谷聡子
  • Organizer: 第 17 回 運動器科学研究会
  • Place of Presentation: 大阪大学中之島センター（大阪府 大阪市）
  • Year and Date: 2016-09-02
• [Presentation] Synoviolin, as a novel factor for understanding obesity and metabolic disorders based on chronic inflammation. (2016)
  • Author(s): Aratani S, Nakajima T
  • Organizer: International Conference on Obesity and Chronic Diseases(WCC 2016)
  • Place of Presentation: Las Vegas(USA)
  • Year and Date: 2016-07-25
  • Int'l Joint Research
• [Presentation] E3 Ubiquitin ligase synoviolin inhibitors has effects on obesity. (2016)
  • Author(s): Aratani S, Fujita H, Yagishita N*, Yokota M, Nishioka K, Nakajima T
  • Organizer: International Conference on Obesity and Chronic Diseases(WCC 2016)
  • Place of Presentation: Las Vegas(USA)
  • Year and Date: 2016-07-25
  • Int'l Joint Research
• [Presentation] Synoviolin, as a new stellar factor for understanding chronic inflammation. (2016)
  • Author(s): Nakajima T
  • Organizer: MOSCOW INTERNATIONAL FORUM OF BONES AND JOINTS DISORDERS/THE INTERNATIONAL SCHOOL CONFERENCE (ISC)
  • Place of Presentation: Moscow(Russia)
  • Year and Date: 2016-04-18
  • Int'l Joint Research
• [Book] New Developments in the Pathogenesis of Rheumatoid Arthritis Synoviolin is a novel pathogenic factor of arthropathy and chronic inflammation. (2016)
  • Author(s): edited by Lazaros I. Sakkas Yagishita N, Aratani S, Fujita H, Yamano Y, Nishioka K, Nakajima T.
  • Total Pages: 151
  • Publisher: INTECH
• [Remarks] 東京医科大学医学総合研究所運動器科学研究部門
  • URL: http://toshinakajima2014.wixsite.com/tokyomed
• [Patent(Industrial Property Rights)] ウォルフラム症候群の治療剤 (2019)
  • Inventor(s): 中島 利博、藤田 英俊、他5名
  • Industrial Property Rights Holder: 中島 利博、藤田 英俊、他5名
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-061768
  • Filing Date: 2019