The elucidation of the molecular mechanisms of NO-mediated muscle atrophy

• Project/Area Number: 21300149
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurophysiology and muscle physiology
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: TAKEDA Shin ichi 独立行政法人国立精神・神経医療研究センター, 神経研究所遺伝子疾患治療研究部, 部長 (90171644)
• Co-Investigator(Kenkyū-buntansha): SUZUKI Yuuko 独立行政法人国立精神・神経医療研究センター, 神経研究所遺伝子疾患治療研究部, 室長 (00342931) ; IMAMURA Michihiro 独立行政法人国立精神・神経医療研究センター, 神経研究所遺伝子疾患治療研究部, 室長 (80221787)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥18,980,000 (Direct Cost: ¥14,600,000、Indirect Cost: ¥4,380,000); Fiscal Year 2011: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2010: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2009: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
• Keywords: 骨格筋 / 筋萎縮 / 一酸化窒素 / 神経型一酸化窒素合成酵素 / 筋肥大 / 萎縮 / 筋ジストロフィー / nNOS / ニトロシル化

Research Abstract

We found that nNOS was involved in not only in the unload-induced muscle atrophy, but also in the overload-induced muscle hypertrophy. nNOS was immediately activated by mechanical overload, and this activation promoted formation of peroxynitrite, a reaction product of nitric oxide with superoxide, which was derived from NADPH oxidase 4(NOX4). These findings may develop therapeutics for muscle atrophy by targeting NO/peroxynitrite.

Research Products

• [Journal Article] Slow-dividing satellite cells retain long-term self-renewal ability in adult muscle (2012)
  • Author(s): Ono Y, Masuda S, Nam HS, Benezra R, Miyagoe-Suzuki Y, Takeda S., Corresponding author
  • Journal Title: J Cell Sci Volume: 125 Issue: 5 Pages: 1309-1317
  • DOI: 10.1242/jcs.096198
  • Peer Reviewed
• [Journal Article] Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle (2011)
  • Author(s): Uezumi A, Ito T, Morikawa D, Shimizu N, Yoneda T, Segawa M, Yamaguchi M, Ogawa R, Matev MM, Miyagoe-Suzuki Y, Takeda S, Tsujikawa K, Tsuchida K, Yamamoto H, Fukada S
  • Journal Title: J Cell Sci Volume: 124(21) Issue: 21 Pages: 3654-3664
  • DOI: 10.1242/jcs.086629
  • Peer Reviewed
• [Journal Article] Hesr1 and Hesr3 are essential to generate undifferentiated quiescent satellite cells and to maintain satellite cell numbers (2011)
  • Author(s): F ukada S, Yamaguchi M, Kokubo H, Ogawa R, Uezumi A, Yoneda T, Matev MM, Motohashi N, Ito T, Zolkiewska A, Johnson RL, Saga Y, Miyagoe-Suzuki Y, Tsujikawa K, Takeda S, Yamamoto H
  • Journal Title: Development Volume: 138 Issue: 21 Pages: 4609-4619
  • DOI: 10.1242/dev.067165
  • Peer Reviewed
• [Journal Article] MURF1 deficiency suppresses unloading-induced effects on osteoblasts and osteoclasts to lead to bone loss (2011)
  • Author(s): Kondo H, Ezura Y, Nakamoto T, Hayata T, Notomi T, Sorimachi H, Takeda S, Noda M
  • Journal Title: J Cell Biochem Volume: 112(12) Issue: 12 Pages: 3525-30
  • DOI: 10.1002/jcb.23327
  • Peer Reviewed
• [Journal Article] Identification of Muscle-Specific MicroRNAs in Serum of Muscular Dystrophy Animal Models : Promising Novel Blood-Based Markers for Muscular Dystrophy (2011)
  • Author(s): M izuno H, Nakamura A, Aoki Y, Ito N, Kishi S, Yamamoto K, Sekiguchi M, Takeda S, Hashido K
  • Journal Title: PLoS One Volume: 30 Issue: 3 Pages: e18388-e18388
  • DOI: 10.1371/journal.pone.0018388
  • Peer Reviewed
• [Journal Article] Matrix metalloproteinase-2 ablation in dystrophin-deficient mdx muscles reduces angiogenesis resulting in impaired growth of regenerated muscle fibers (2011)
  • Author(s): M iyazaki D, Nakamura A, Fukushima K, Yoshida K, Takeda S, Ikeda S
  • Journal Title: Hum Mol Genet Volume: 20 Issue: 9 Pages: 1787-1799
  • DOI: 10.1093/hmg/ddr062
  • Peer Reviewed
• [Journal Article] Crosstalk between Glucocorticoid Receptor and Nutritional Sensor mTOR in Skeletal Muscle (2011)
  • Author(s): S himizu N, Yoshikawa N, Ito N, Maruyama T, Suzuki Y, Takeda S, Nakae J, Tagata Y, Nishitani S, Takehana K, Sano M, Fukuda K, Suematsu M, Morimoto C, Tanaka H
  • Journal Title: Cell Metab Volume: 13 Issue: 2 Pages: 170-182
  • DOI: 10.1016/j.cmet.2011.01.001
  • Peer Reviewed
• [Journal Article] MURF1 deficiency suppresses unloading-induced effects on osteoblasts and osteoclasts to lead to bone loss (2011)
  • Author(s): Kondo H, et.al.
  • Journal Title: Gene Ther Volume: 18 Issue: 9 Pages: 910-919
  • DOI: 10.1038/gt.2011.36
  • Peer Reviewed
• [Journal Article] Crosstalk between Glucocorticoid Receptor and Nutritional Sensor mTOR in Skeletal Muscle. (2011)
  • Author(s): Shimizu N, Yoshikawa N, Ito N, Maruyama T, Suzuki Y, Takeda S, Nakae J, Tagata Y, Nishitani S, Takehana K, Sano M, Fukuda K, Suematsu M, Morimoto C, Tanaka H
  • Journal Title: Cell Metab. Volume: 13 Pages: 170-182
  • Peer Reviewed
• [Journal Article] Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle (2010)
  • Author(s): Uezumi A, Fukuda S, Yamamoto N, Takeda S, Tsuchida K
  • Journal Title: Nat Cell Biol Volume: 12 Issue: 2 Pages: 143-152
  • DOI: 10.1038/ncb2014
  • Peer Reviewed
• [Journal Article] Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle (2010)
  • Author(s): Uezumi A, Fukuda S, Yamamoto N, Takeda S, Tsuchida K
  • Journal Title: Nat Cell Biol. 12 Pages: 143-52
  • Peer Reviewed
• [Journal Article] Ubiquitin ligase Cbl-b is a negative regulator for IGF-1 signaling during muscle atrophy caused by unloading (2009)
  • Author(s): N akao R, Hirasaka K, Goto J, Ishidoh K, Yamada C, Ohno A, Okumura Y, Nonaka I, Yasutomo K, Baldwin KM, Kominami E, Higashibata A, Nagano K, Tanaka K, Yasui N, Mills EM, Takeda S, Nikawa T
  • Journal Title: Mol Cell Biol Volume: 17 Issue: 17 Pages: 4798-4811
  • DOI: 10.1128/mcb.01347-08
  • Peer Reviewed
• [Journal Article] Generation of transplantable, functional satellite-like cells from mouse embryonic stem cells (2009)
  • Author(s): C hang H, Yoshimoto M, Umeda K, Iwasa T, Mizuno Y, Fukada S, Yamamoto H, Motohashi N, Miyagoe-Suzuki Y, Takeda S, Heike T, Nakahata T
  • Journal Title: FASEB J Volume: 23 Issue: 6 Pages: 1907-1919
  • DOI: 10.1096/fj.08-123661
  • Peer Reviewed
• [Journal Article] Ubiquitin ligase Cbl-b is a negative regulator for IGF-1 signaling during muscle atrophy caused by unloading (2009)
  • Author(s): Nakao R, Hirasaka K, Goto J, Ishidoh K, Yamada C, Ohno A, Okumura Y, Nonaka I, Yasutomo K, Baldwin KM, Kominami E, Higashibata A, Nagano K, Tanaka K, Yasui N, Mills EM, Takeda S, Nikawa T
  • Journal Title: Mol Cell Biol. 17 Pages: 4798-4811
  • Peer Reviewed
• [Journal Article] Generation of transplantable, functional satellite-like cells from mouse embryonic stem cells (2009)
  • Author(s): Chang H, Yoshimoto M, Umeda K, Iwasa T, Mizuno Y, Fukada S, Yamamoto H, Motohashi N, Miyagoe-Suzuki Y, Takeda S, Heike T, Nakahata T
  • Journal Title: FASEB J. 23 Pages: 1907-1919
  • Peer Reviewed
• [Journal Article] (2009)
  • Author(s): 鈴木友子, 武田伸一
  • Journal Title: 骨格筋, 炎症・再生医学事典(朝倉書店) Pages: 453-456
• [Presentation] Molecular mechanism of muscle hypertrophy-NO/peroxynitrite-induced activation of TRPV1- (2012)
  • Author(s): Takeda S
  • Organizer: University of Geneva
  • Place of Presentation: Geneva, Switzerland
  • Year and Date: 2012-03-21
• [Presentation] Molecular mechanism of muscle hypertrophy-NO/peroxynitrite-induced activation of TRPV1- (2012)
  • Author(s): Takeda S
  • Organizer: University of Geneva
  • Place of Presentation: University of Geneva, Geneva, Switzerland(招待講演)
  • Year and Date: 2012-03-21
• [Presentation] 骨格筋神経型一酸化窒素合成酵素(nNOS)は過負荷によって活性化され,タンパク質合成の活性化を介して筋肥大の進行を制御している (2011)
  • Author(s): 伊藤尚基,工藤明,鈴木友子,武田伸一
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-16
• [Presentation] 骨格筋神経型一酸化窒素合成酵素(nNOS)は過負荷によって活性化され,タンパク質合成の活性化を介して筋肥大の進行を制御している (2011)
  • Author(s): 伊藤尚基
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜,横浜
  • Year and Date: 2011-12-16
• [Presentation] nNOS is an essential mediator for mechanical overload-induced muscle hypertrophy (2011)
  • Author(s): N Ito, K. Akira, Y Suzuki, U Ruegg, S Takeda
  • Organizer: International Conference On Muscle Wasting
  • Place of Presentation: Ascona, Switzerland
  • Year and Date: 2011-09-20
• [Presentation] nNOS is an essential mediator for mechanical overload-induced muscle hypertrophy (2011)
  • Author(s): N Ito
  • Organizer: International Conference On Muscle Wasting
  • Place of Presentation: Centro Stefano Franscini, Ascona, Switzerland
  • Year and Date: 2011-09-20
• [Presentation] 骨格筋の幹細胞と再生の分子機構 (2011)
  • Author(s): 武田伸一
  • Organizer: 第3回シグナルネットワーク研究会
  • Place of Presentation: 東京
  • Year and Date: 2011-05-27
• [Presentation] 骨格筋の幹細胞と再生の分子機構 (2011)
  • Author(s): 武田伸一
  • Organizer: 第3回シグナルネットワーク研究会
  • Place of Presentation: 東京大学医科学研究所,東京(招待講演)
  • Year and Date: 2011-05-27
• [Presentation] Identification of a long-term self-renewable population in activated satellite cells. The molecular and cellular mechanisms regulating skeletal muscle, development and regeneration (2011)
  • Author(s): O no Y, Masuda S, Miyagoe-Suzuki Y, Takeda S
  • Organizer: EMBO conference series
  • Place of Presentation: Wiesbaden, Germany
  • Year and Date: 2011-05-13
• [Presentation] Identification of a long-term self-renewable population in activated satellite cells (2011)
  • Author(s): Ono Y
  • Organizer: The molecular and cellular mechanisms regulating skeletal muscle, development and regeneration, EMBO conference series
  • Place of Presentation: DORINT PALLAS HOTEL Wiesbaden, Germany
  • Year and Date: 2011-05-13
• [Presentation] Isolation and characterization of a long-term self-renewable population in activated satellite cells (2011)
  • Author(s): Takeda S
  • Organizer: 4^<th> International congress of Myology
  • Place of Presentation: Lille, France
  • Year and Date: 2011-05-11
• [Presentation] Isolation and characterization of a long-term self-renewable population in activated satellite cells (2011)
  • Author(s): Takeda S
  • Organizer: 4^<th> International congress of Myology
  • Place of Presentation: Lille Grand Palais, France(招待講演)
  • Year and Date: 2011-05-11
• [Presentation] 骨格筋神経型一酸化窒素合成酵素(nNOS)過負荷によって活性化され,タンパク質合成の活性化を介して筋肥大の進行を制御している (2010)
  • Author(s): 伊藤尚基,工藤明,鈴木友子,武田伸一
  • Organizer: 第33回日本分子生物学会年会,第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-08
• [Presentation] 骨格筋神経型一酸化窒素合成酵素(nNOS)過負荷によって活性化され, タンパク質合成の活性化を介して筋肥大の進行を制御している. (2010)
  • Author(s): 伊藤尚基, 工藤明, 鈴木友子, 武田伸一
  • Organizer: 第33回日本分子生物学会年会第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸神戸ポートアイランド
  • Year and Date: 2010-12-08
• [Presentation] nNOSは筋萎縮と筋肥大を制御するメカノセンサーである (2010)
  • Author(s): 武田伸一,伊藤尚基,鈴木友子
  • Organizer: 第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-07
• [Presentation] nNOSは筋萎縮と筋肥大を制御するメカノセンサーである. (2010)
  • Author(s): 武田伸一, 伊藤尚基, 鈴木友子
  • Organizer: 第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸神戸ポートアイランド
  • Year and Date: 2010-12-07
• [Presentation] 骨格筋神経型一酸化窒素合成酵素は過負荷によって活性化され、タンパク質合成・分解の制御を介して筋肥大を促進する (2010)
  • Author(s): 伊藤尚基,工藤明,鈴木友子,武田伸一
  • Organizer: 第31回日本炎症・再生医学会
  • Place of Presentation: 新宿
  • Year and Date: 2010-08-05
• [Presentation] 骨格筋神経型一酸化窒素合成酵素は過負荷によって活性化され、タンパク質合成・分解の制御を介して筋肥大を促進する. (2010)
  • Author(s): 伊藤尚基, 工藤明, 鈴木友子, 武田伸一
  • Organizer: 第31回日本炎症・再生医学会
  • Place of Presentation: 新宿京王プラザホテル
  • Year and Date: 2010-08-05
• [Presentation] 筋萎縮と筋肥大の分子機構を巡ってMolecular mechanisms of muscle atrophy and hypertrophy (2010)
  • Author(s): 武田伸一
  • Organizer: 第3回上肢の神経機能回復セミナー
  • Place of Presentation: 秋田
  • Year and Date: 2010-05-14
• [Presentation] 筋萎縮と筋肥大の分子機構を巡ってMolecular mechanisms of muscleatrophy and hypertrophy. (2010)
  • Author(s): 武田伸一
  • Organizer: 第3回上肢の神経機能回復セミナー
  • Place of Presentation: 秋田角館広域交流センター
  • Year and Date: 2010-05-14
• [Presentation] Neuronal nitric oxide synthase is an essential mediator for muscle hypertrophy (2009)
  • Author(s): I to N, Ampong BN, Kudo A, Miyagoe-Suzuki Y, Takeda S
  • Organizer: International Congress of Physiological Sciences
  • Place of Presentation: Kyoto
  • Year and Date: 2009-07-29
• [Presentation] Neuronal nitric oxide synthase is an essential mediator for muscle hypertrophy (2009)
  • Author(s): Ito N, Ampong BN, Kudo A, Miyagoe-Suzuki Y, Takeda S
  • Organizer: International Congress of Physiological Sciences
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2009-07-29
• [Book] Mechanobiology in skeletal muscle : conversion of mechanical information into molecular signal. Mechanosensing Biology (2010)
  • Author(s): Miyagoe-Suzuki Y, Takeda S
  • Publisher: Springer Japan
• [Book] Mechanosensing Biology(ed.Masaki Noda) (2010)
  • Author(s): Miyagoe-Suzuki Y, Takeda S
  • Total Pages: 219
  • Publisher: Springer Japan
• [Book] 骨格筋.炎症・再生医学事典 (2009)
  • Author(s): 鈴木友子,武田伸一
  • Publisher: 朝倉書店
• [Patent(Industrial Property Rights)] 筋増加剤及び筋増加物質のスクリーニング法 (2012)
  • Inventor(s): 武田伸一,伊藤尚基, Urs T. Ruegg,鈴木友子
  • Industrial Property Rights Holder: NCNP
  • Industrial Property Number: 2012-063182
  • Filing Date: 2012-03-21
• [Patent(Industrial Property Rights)] 筋増加剤及び筋増加物質のスクリーニング法 (2012)
  • Inventor(s): 武田伸一, 伊藤尚基, Urs T.Ruegg, 鈴木友子
  • Industrial Property Rights Holder: NCNP
  • Industrial Property Number: 2012-063182
  • Filing Date: 2012-03-21
• [Patent(Industrial Property Rights)] 筋肥大を促進する物質又は因子のスクリーニング法 (2011)
  • Inventor(s): 武田伸一,伊藤尚基, Urs T. Ruegg,鈴木友子
  • Industrial Property Rights Holder: NCNP
  • Industrial Property Number: 2011-200716
  • Filing Date: 2011-09-24
• [Patent(Industrial Property Rights)] 筋肥大を促進する物質又は因子のスクリーニング法 (2011)
  • Inventor(s): 武田伸一, 伊藤尚基, Urs T.Ruegg, 鈴木友子
  • Industrial Property Rights Holder: NCNP
  • Industrial Property Number: 2011-200716
  • Filing Date: 2011-09-24