Elucidation of the molecular mechanisms of muscle atrophy

• Project/Area Number: 21200023
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research a proposed research project)
• Allocation Type: Single-year Grants
• Research Field: General medical chemistry; Applied health science
• Research Institution: Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology
• Principal Investigator: SHIGEMOTO Kazuhiro 地方独立行政法人東京都健康長寿医療センター(東京都健康長寿医療センター研究所), 東京都健康長寿医療センター研究所, 研究部長 (40284400)
• Co-Investigator(Kenkyū-buntansha): KUBO Sachiho 地方独立行政法人東京都健康長寿医療センター(東京都健康長寿医療センター研究所), 東京都健康長寿医療センター研究所, 助手 (00280769) ; MIYAZAKI Tsuyoshi 地方独立行政法人東京都健康長寿医療センター(東京都健康長寿医療センター研究所), 東京都健康長寿医療センター研究所, 研究員 (50376480) ; YAMADA Shigeru 地方独立行政法人東京都健康長寿医療センター(東京都健康長寿医療センター研究所), 東京都健康長寿医療センター研究所, 研究員 (50508679)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥30,940,000 (Direct Cost: ¥23,800,000、Indirect Cost: ¥7,140,000); Fiscal Year 2011: ¥10,010,000 (Direct Cost: ¥7,700,000、Indirect Cost: ¥2,310,000); Fiscal Year 2010: ¥10,010,000 (Direct Cost: ¥7,700,000、Indirect Cost: ¥2,310,000); Fiscal Year 2009: ¥10,920,000 (Direct Cost: ¥8,400,000、Indirect Cost: ¥2,520,000)
• Keywords: 筋萎縮 / 神経筋シナプス / 逆行性シグナル / 運動神経細胞 / 筋線維 / 神経筋接合部 / 疾患モデル動物 / ノックインマウス / 神経細胞栄養因子

Research Abstract

We found that MuSK molecules, which are expressed at post synaptic membrane of NMJs, mediates unknown retrograde signaling which regulate presynaptic functions. We generated mouse expressed-genes database for atrophy-induced muscles to find the retrograde-signaling molecules.

Research Products

• [Journal Article] 3,4-Diaminopyridine improves neuromuscular transmission in a MuSK antibody-induced mouse model of myasthenia gravis (2012)
  • Author(s): Mori, S. , Kishi, M., Kubo, S., Akiyoshi, T., Yamada, S., Miyazaki, T., Konishi, T., Maruyama, N., and Shigemoto, K.
  • Journal Title: Journal of neuroimmunology Volume: 245 Issue: 1-2 Pages: 75-78
  • DOI: 10.1016/j.jneuroim.2012.02.010
  • Peer Reviewed
• [Journal Article] Antibodies against muscle-specific kinase impair both presynaptic and postsynaptic functions in a murine model of myasthenia gravis (2012)
  • Author(s): Mori, S., Kubo, S., Akiyoshi, T., Yamada, S., Miyazaki, T., Hotta, H., Desaki, J., Kishi, M., Konishi, T., Nishino, Y., Miyazawa, A., Maruyama, N., and Shigemoto, K.
  • Journal Title: The American journal of pathology Volume: 180 Pages: 798-810
  • Peer Reviewed
• [Journal Article] Divalent and monovalent autoantibodies cause dysfunction of MuSK by distinct mechanisms in a rabbit model of myasthenia gravis (2012)
  • Author(s): Mori, S. , Yamada, S., Kubo, S. , Chen, J., Matsuda, S. , Shudou, M. , Maruyama, N., and Shigemoto, K.
  • Journal Title: Journal of neuroimmunology Volume: 244 Issue: 1-2 Pages: 1-7
  • DOI: 10.1016/j.jneuroim.2011.12.005
  • Peer Reviewed
• [Journal Article] Antibodies against muscle-specific kinase impair both presynaptic and postsynaptic functions in a murine model of myasthenia gravis (2012)
  • Author(s): Mori S, Kubo S, Akiyoshi T, Yamada S, Miyazaki T, Hotta H, Desaki J, Kishi M, Konishi T, Nishino Y, Miyazawa A, Maruyama N, Shigemoto K
  • Journal Title: The American Journal of Pathology Volume: 180 Issue: 2 Pages: 617-28
  • DOI: 10.1016/j.ajpath.2011.10.031
  • Peer Reviewed
• [Journal Article] Galectin-7 as a marker of cholesteatoma residue and its detection during surgery by immunofluorescent method --- A prelinimary study. (2012)
  • Author(s): 高木大樹
  • Journal Title: Ontology and Neurotology Volume: 33 Issue: 3 Pages: 396-399
  • DOI: 10.1097/mao.0b013e3182488021
  • Peer Reviewed
• [Journal Article] サルコペニアの発症機構 (2011)
  • Author(s): 重本和宏,森秀一,宮崎剛,久保幸穂
  • Journal Title: 神経内科 Volume: 75(6) Pages: 584-588
• [Journal Article] シナプスを介したサルコペニアの発症メカニズムとバイオマーカー (2011)
  • Author(s): 重本和宏、森秀一、宮崎剛、久保幸穂
  • Journal Title: 日本老年医学会雑誌 Volume: 48(1) Pages: 42-43
  • NAID: 10030468993
• [Journal Article] 運動神経細胞とサルコペニア (2011)
  • Author(s): 重本和宏、森秀一、宮崎剛、久保幸穂
  • Journal Title: Modern Physician Volume: 131,No.11 Pages: 1308-11
• [Journal Article] Establishment and characterization of hepatocytes from an Immortomouse/SMP30/GNL knockout mouse hybrid lacking vitamin C to study vitamin C transport (2011)
  • Author(s): Amano, A., Handa, S., Aigaki, T., Shigemoto, K., Maruyama, N., Ishigami, A.
  • Journal Title: Journal of biochemistry Volume: 150 Issue: 6 Pages: 671-678
  • DOI: 10.1093/jb/mvr109
  • Peer Reviewed
• [Journal Article] シナプスを介したサルコペニアの発症メカニズムとバイオマーカー (2011)
  • Author(s): 重本和宏, 森秀一、宮崎剛、久保幸穂
  • Journal Title: 日本老年医学会雑誌 Volume: 48 Pages: 42-3
  • NAID: 10030468993
• [Journal Article] サルコペニアの発症機構 (2011)
  • Author(s): 重本和宏, 森秀一、宮崎剛、久保幸穂
  • Journal Title: 日本老年医学会雑誌 Volume: 75 Pages: 584-8
• [Journal Article] Muscle weakness and neuromuscular junctions in aging and disease (2010)
  • Author(s): Shigemoto, K., Kubo, S., Mori, S., Yamada, S., Akiyoshi, T., and Miyazaki, T.
  • Journal Title: Geriatr Gerontol Int 10 Suppl Volume: 1 Issue: s1 Pages: 137-147
  • DOI: 10.1111/j.1447-0594.2010.00608.x
  • NAID: 10027273521
  • Peer Reviewed
• [Journal Article] 抗MuSK抗体 (2010)
  • Author(s): 大田潔江,大田光煕,重本和宏、(他一名)
  • Journal Title: 日本臨床 Volume: Vol.685
• [Journal Article] 神経筋接合部の異常と筋萎縮 (2010)
  • Author(s): 重本和宏,森秀一,久保幸穂,山田茂,秋好沢諭,宮崎剛
  • Journal Title: メジカルビュー社老年医学 Volume: update 2010-2011 Pages: 135-144
• [Journal Article] Neutrophil CD64 expression as a diagnostic marker for local infection and crystal-induced arthritis. (2010)
  • Author(s): Doi, T., Miyazaki, T., Nishino, J., Tanaka, S., Matsui, T., Komiya, A., Yamamoto, S., Tokimura, F., Mori, T., Nishimura, K., Katoh, N., Hasegawa, J., Omata, Y., Matsushita, T, Tohma, S
  • Journal Title: Mod.Rheumatol. Volume: 20(6) Pages: 573-579
  • NAID: 10027647433
  • Peer Reviewed
• [Journal Article] Regulation of apoptosis and activity of the osteoclast. (2010)
  • Author(s): Miyazaki, T, Tanaka, S.
  • Journal Title: Immun.Endoc.Metab.Agents in Med.Chem. Volume: 10(2) Pages: 100-107
  • Peer Reviewed
• [Journal Article] Muscle weakness and neuromuscular junction in aging and disease (2010)
  • Author(s): Shigemoto, K., Kubo, S., Mori, S., Yamada, S., Akiyoshi, T., Miyazaki, T.
  • Journal Title: Geriatr.Gerintol.Int. Volume: 10
  • NAID: 10027273521
  • Peer Reviewed
• [Journal Article] 神経筋接合部位の異常と筋力低下 (2009)
  • Author(s): 重本和宏、久保幸穂、丸山直記
  • Journal Title: 日本老年医学会雑誌 Volume: 46(2) Pages: 106-113
  • NAID: 10024963928
• [Journal Article] サルコペニア(加齢性筋肉減少症)とそのバイオマーカー (2009)
  • Author(s): 重本和宏、丸山直記
  • Journal Title: 老年医学 Volume: 47(6) Pages: 733-735
• [Journal Article] The role of zinc finger protein 521/early hematopoietic zinc finger protein in erythroid cell differentiation. (2009)
  • Author(s): Matsubara, E., Sakai, I., Yamanouchi, J. , Fujiwara, H., Yakushijin, Y., Hato, T., Shigemoto, K., Yasukawa, M.
  • Journal Title: J Biol Chem 284 Pages: 3480-3487
  • Peer Reviewed
• [Journal Article] Rheumatoid Arthritis associated with osteopetrosis. (2009)
  • Author(s): Yuho Kadono, Sakae Tanaka, Jinju Nishino, Keita Nishimura, Ichiro Nakamura, Tsuyoshi Mivazaki, Hiroshi Takayanagi, Kozo Nakamura
  • Journal Title: Mod Rheumatol 19 Pages: 687-690
  • Peer Reviewed
• [Journal Article] The antiapoptotic protein Bcl-xL negatively regulates the bone-resorbing activity of osteoclasts in mice. (2009)
  • Author(s): Iwasawa M, Miyazaki T, Nagase Y, Akiyama T, Kadono Y, Nakamura M, Oshima Y, Yasui T, Matsumoto T, Nakamura T, Kato S, Hennighausen L, Nakamura K, Tanaka S
  • Journal Title: J Clin Invest 19 Pages: 3149-59
  • Peer Reviewed
• [Journal Article] Reverse Transfection Using Gold Nanoparticle. (2009)
  • Author(s): Yamada S, Fujita S, Uchimura E, Miyake M, Miyake J
  • Journal Title: Methods Mol Biol 544 Pages: 609-616
  • Peer Reviewed
• [Journal Article] 神経筋接合部位の異常と筋力低下. (2009)
  • Author(s): 重本和宏、久保幸穂、丸山直記
  • Journal Title: 日本老年医学会雑誌 46 Pages: 106-113
  • NAID: 10024963928
• [Journal Article] サルコペニア(加齢性筋肉減少症)とそのバイオマーカー (2009)
  • Author(s): 重本和宏、丸山直記
  • Journal Title: 老年医学 47 Pages: 733-735
• [Journal Article] 骨・関節と加齢 (2009)
  • Author(s): 宮崎剛、田中栄
  • Journal Title: ANTI-AGING MEDICEIN 6 Pages: 70-74
• [Presentation] 抗MuSK抗体陽性重症筋無力症の発症メカニズムに基づく治療薬の検討 (2012)
  • Author(s): 森秀一, 久保幸穂, 岸雅彦, 小西哲郎, 重本和宏
  • Organizer: 第53回日本神経学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2012-05-25
• [Presentation] A new synchronized model of myasthenia gravis caused by anti-MuSK antibodies (2012)
  • Author(s): Shigemoto K
  • Organizer: International Conference on Nervous System Autoimmunity
  • Place of Presentation: Bangalore, India
  • Year and Date: 2012-01-27
• [Presentation] A new synchronized model of myasthenia gravis caused by and-MuSK antibodies (2012)
  • Author(s): Shigemoto, K.
  • Organizer: International Conference on Nervous System Autoimmunity
  • Place of Presentation: Bangalore, India
• [Presentation] Distinct mechanisms between divalent and monovalent MuSK antibodies involved with dysfunction of MuSK leading to myasthenia gravis (2011)
  • Author(s): Mori S, Kubo S, Yamada S, Miyazaki T, Shigemoto K
  • Organizer: Society for Neuroscience
  • Place of Presentation: Washington DC
  • Year and Date: 2011-11-15
• [Presentation] サルコペニアのメカニズム解明に向けて (2011)
  • Author(s): 重本和宏
  • Organizer: 第33回日本基礎老化学会シンポジウム
  • Place of Presentation: 名古屋大学
  • Year and Date: 2011-10-08
• [Presentation] MuSKとDok-7の相互作用は神経筋シナプスの維持に重要である (2011)
  • Author(s): 森秀一, 重本和宏
  • Organizer: 第66回日本体力医学会大会
  • Place of Presentation: 下関
  • Year and Date: 2011-09-17
• [Presentation] Distinct mechanisms between divalent and monovalent MuSK antibodies involved with dysfunction of MuSK leading to myasthenia gravis (2011)
  • Author(s): Mori S, Kubo S, Yamada S, Miyazaki T, Shigemoto K.
  • Organizer: 第34回日本神経科学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2011-09-12
• [Presentation] Distinct mechanisms between divalent and monovalent MuSK antibodies involved with dysfunction of MuSK leading to myasthenia gravis (2011)
  • Author(s): Mori S, Kubo S, Yamada S, Miyazaki T, Shigemoto K.
  • Organizer: Society for Neuroscience
  • Place of Presentation: Washington, D.C.
• [Presentation] サルコペニアのメカニズム解明に向けて (2011)
  • Author(s): 重本和宏
  • Organizer: 第33回日本基礎老化学会シンポジウム
  • Place of Presentation: 野田
• [Presentation] Strategy to treatment of myasthenia gravis caused by MuSK antibodies using a synchronized experimental animal model (2010)
  • Author(s): Mori S, Kubo S, Akiyoshi T, Yamada S, Miyazaki T, Shigemoto K.
  • Organizer: Society for Neuroscience 2010
  • Place of Presentation: San Diego
  • Year and Date: 2010-11-17
• [Presentation] New strategy to treatment of myasthenia gravis caused by MuSK antibodies using a synchronized experimental animal model (2010)
  • Author(s): Mori S, Kubo S, Akiyoshi T, Yamada S, Miyazaki T, Shigemoto K.
  • Organizer: 第33回神経科学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-09-03
• [Presentation] 筋は逆行性シグナルにより筋・運動神経を維持する (2010)
  • Author(s): 森秀一, 久保幸穂, 秋好沢諭, 山田茂, 宮崎剛, 重本和宏
  • Organizer: 第33回日本基礎老化学会大会
  • Place of Presentation: 名古屋
  • Year and Date: 2010-06-18
• [Presentation] Complement activation is dispensable for myasthenia gravis caused by MuSK antibodies (2010)
  • Author(s): Shigemoto K, Mori S, Kubo S, Akiyoshi T, Yamada S, Miyazaki T.
  • Organizer: 10^<th> International Congress of Neuroimmunology 2010
  • Place of Presentation: Barcelona, Spain
• [Presentation] Mouse lacking in intracellular superoxide dismutase increased reactive oxygen spices in osteoblasts and suppressed osteoblastic ability leading to osteoporotic phenotypes in bone. (2010)
  • Author(s): Saita, Y., Mojiri, H., Tsuda, C., Miyazaki, T., Morikawa, D., Kaneko, K, Shimizu, T.
  • Organizer: IOF World Congress on Osteoporosis & 10^<th> European Congress on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis
  • Place of Presentation: Italy
• [Presentation] New strategy to treatment of myasthenia gravis caused by MuSK antibodies using a synchronized experimental animal model (2010)
  • Author(s): Mori, S., Kubo, S., Akiyoshi, T., Yamada, S., Miyazaki, T., Shigemoto, K.
  • Organizer: 第33回日本神経科学会大会
  • Place of Presentation: 神戸
• [Presentation] Intracellular superoxide dismutase deficiency decreased bone mass in vivo by impairment of cell viability and redox balance in osteoblasts. (2010)
  • Author(s): Saita, Y., Nojiri, H., Tsuda, C., Miyazaki, T., Morikawa, D., Kaneko, K, Shimizu, T.
  • Organizer: 32^<nd> Annual Meeting of the American Society for Bone and Mineral Research
  • Place of Presentation: Toronto
• [Presentation] Complement activation is dispensable for myasthenia gravis caused by MuSK antibodies. (2010)
  • Author(s): Shigemoto, K., Mori, S., Kubo, S., Akiyoshi, T., Yamada, S., Miyazaki, T
  • Organizer: 10^<th> International Congress of Neuroimmunology
  • Place of Presentation: Barcelona
• [Presentation] Strategy to treatment of myasthenia gravis caused by MuSK antibodies using a synchronized experimental animal model. (2010)
  • Author(s): Mori, S., Kubo, S., Akiyoshi, T., Yamada, S., Miyazaki, T., Shigemoto, K
  • Organizer: Society for Neuroscience 2010
  • Place of Presentation: San Diego
• [Presentation] Activation of complement is indispensable for myasthenia gravis caused by MuSK antibodies (2009)
  • Author(s): Mori S, Kubo S, Akiyoshi T, Yamada S, Miyazaki T, Shigemoto K.
  • Organizer: Society for Neuroscience 2009
  • Place of Presentation: Chicago
  • Year and Date: 2009-10-17
• [Presentation] Activation of complement is indispensable for myasthenia gravis caused by MuSK antibodies. (2009)
  • Author(s): Mori S, Kubo S, Akivoshi T, Yamada S, Miyazaki T, Shigemoto K.
  • Organizer: Society for Neuroscience 2009
  • Place of Presentation: Chicago
  • Year and Date: 2009-10-17
• [Presentation] Activation of complement is indispensable for myasthenia gravis caused by MuSK antibodies (2009)
  • Author(s): Mori S, Kubo S, Akiyoshi T, Yamada S, Shigemoto K.
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋
  • Year and Date: 2009-09-19
• [Presentation] Activation of complement is indispensable for myasthenia gravis caused by MuSK antibodies. (2009)
  • Author(s): Mori S, Kubo S, Akiyoshi T, Yamada S, Shigemoto K.
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋
  • Year and Date: 2009-09-19
• [Presentation] MuSKは神経筋シナプスの維持に重要である～研究モデル動物の確立～ (2009)
  • Author(s): 森秀一, 久保幸穂, 秋好沢諭, 山田茂, 宮崎剛, 重本和宏
  • Organizer: 第32回日本基礎老化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2009-06-27
• [Presentation] Anti-apoptotic Molecule Bcl-xL regulates osteoclastic bone resorption via extracellular matrix component expression. (2009)
  • Author(s): Tsuyoshi Miyazaki, Mitsuyasu Iwasawa, Yuichi Nagase, Yuho Kadono, Lothar Henninghausen, Takashi Nakamura, Shigeaki Kato, Kozo Nakamura, Sakae Tanaka
  • Organizer: The 26^<th> NAITO Conference on Osteobioloty
  • Place of Presentation: Awaji Yumebutai, Hyogo
• [Presentation] Copper/zinc superoxide dismutase deficiency causes low turnover osteopenia (2009)
  • Author(s): Chizuru Tsuda, Hidetoshi Nojiri, Yoshitomo Saita, Tsuyoshi Miyazaki, Yusuke Ozawa, Yoshihiro Noda, Daichi Morikawa, Takahiko Shimizu
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: 横浜
• [Presentation] 骨関節感染症における好中球上CD64分子発現の発現計測の有用性-第二報告- (2009)
  • Author(s): 西野仁寿、松井利浩、小宮明子、田中栄、門野夕峰、中村正樹、宮崎剛、當間重人
  • Organizer: 第53回日本リウマチ学会総会・学術集会
  • Place of Presentation: 東京
• [Presentation] [関節リウマチにおける結晶アルギニンデイミナーゼ4(PAD4)及び抗PAD4抗体の検討 (2009)
  • Author(s): 木村直樹、宮崎剛、杉原毅彦
  • Organizer: 第53回日本リウマチ学会総会・学術集会
  • Place of Presentation: 東京
• [Presentation] 結晶性関節炎と感染性関節炎の鑑別における好中球CD64値の有用性 (2009)
  • Author(s): 滝田泰人、西野仁寿、濱路博、宮崎型、松井利浩、小宮明子、田中栄、時村文秋、當間重人
  • Organizer: 第82回日本整形外科学会学術総会
  • Place of Presentation: 博多
• [Presentation] 高齢者TKAにおけるmini-mental state examinationを用いた術前認知機能評価の有用性 (2009)
  • Author(s): 宮本恵成、濱路博、宮崎剛、穴水依人、時村文秋、石橋英明、山本精三
  • Organizer: 第82回日本整形外科学会学術総会
  • Place of Presentation: 博多
• [Book] 運動神経細胞とサルコペニア (2011)
  • Author(s): 重本和宏, 森秀一、宮崎剛、久保幸穂
  • Total Pages: 2
  • Publisher: 新興医学出版社
• [Book] 老年医学update 2010-2011 (2010)
  • Author(s): 重本和宏、森秀一、久保幸穂、山田茂、秋好沢諭、宮崎剛
  • Total Pages: 184
  • Publisher: メディカルビュー社
• [Book] Myasthenia gravis Diseas Mechanisms and Immune Intervention-Chaper 17.The Tmmunopathogenesis of Experimental Autoimmune Myasthenia Gravis Induced by Autoantibodies against Muscle-specific kinase (2009)
  • Author(s): Shigemoto, K. Kubo, S. Mori. S. Yamada, S. Miyazaki, T. Akiyoshi, T and Maruyama, S.
  • Publisher: Linus Publication, Inc.
• [Book] Myasthenia gravis Disease Mechanisms and Immune Intervention. (2009)
  • Author(s): Shigemoto, K.Kubo, S.Mori. S.Yamada, S.Miyazaki, T.Akiyoshi, T, Maruyama, S.
  • Publisher: Linus Publication, Inc.
• [Remarks] The Jackson Laboratory, USA
  • URL: http://jaxmice.jax.org/news/2012/Myasthenia_gravis.html
• [Remarks] The Jackson Laboratory, USA Podcast
  • URL: http://jaxmice.jax.org/multimedia/podcasts/20120524-Shigemoto.mp3
• [Remarks] 東京都健康長寿医療センター研究所老年病研究チーム運動器医学
  • URL: http://www.tmghig.jp/J_TMIG/j_research/DA33.html
• [Remarks]
  • URL: http://www.tmghig.jp/J_TMIG/j_research/DA33.html