Mitochondria is a key signal inducer for unloading stress toward muscle atrophy

• Project/Area Number: 24390355
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: The University of Tokushima
• Principal Investigator: NIKAWA Takeshi 徳島大学, ヘルスバイオサイエンス研究部, 教授 (20263824)
• Co-Investigator(Kenkyū-buntansha): SOKABE Masahiro 名古屋大学, 大学院医学研究科, 教授 (10093428) ; KOBAYASHI Takeshi 名古屋大学, 大学院医学研究科, 助教 (40402565) ; SUZUKI Yutaka 東京大学, 大学院新領域創成科学研究科, 教授 (40323646)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2014: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2013: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
• Keywords: 筋萎縮 / メカノセンシング / ユビキチンリガーゼ / ミトコンドリア / メカノセンサー / 酸化ストレス / 無重力 / 次世代シークエンサー

Outline of Final Research Achievements

Ubiquitin ligase Cbl-b plays a crucial role in disuse-mediated muscle atrophy: Cbl-b caused ubiquitination and subsequent degradation of IRS-1, resulting in skeletal muscle atrophy. Since Cbl-b in skeletal muscle is preferentially expressed under unloading conditions, we hypothesized that elucidating the regulation pathway of Cbl-b expression leads to the clarification of the sensing mechanism for unloading stress. Here we report the mechanism of sensing for microgravity, using rat or mouse skeletal myotubes cultured under unloading conditions. Microgravity or simulated microgravity conditions significantly caused decrease in myotube diameter, indicating that skeletal muscle myotubes per se can sense microgravity stress. Furthermore, there was a potent oxidative stress responsive element from -110 to -60 bp of the Cbl-b promoter. We suggest that unloading stress induced muscle atrophy through oxidative stress-mediated Cbl-b expression and mitochondria dysfunction.

Research Products

• [Journal Article] Atypical expression of circadian clock genes in denervated mouse skeletal muscle. (2015)
  • Author(s): Nakao R, Yamamoto S, Horikawa K, Yasumoto Y, Nikawa T, Mukai C, Oishi K
  • Journal Title: Chronobiology International Volume: in press
  • Peer Reviewed
• [Journal Article] Osteoactivin attenuates skeletal muscle fibrosis after distraction osteogenesis by promoting extracellular matrix degradation/remodeling. (2015)
  • Author(s): Tonogai I, Takahashi M, Yukata K, Sato R, Nikawa T, Yasui N, Sairyo K.
  • Journal Title: J Pediatr Orthop B Volume: 24 Issue: 2 Pages: 162-169
  • DOI: 10.1097/bpb.0000000000000117
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• [Journal Article] Flavones inhibit LPS-induced atrogin-1/MAFbx expression in mouse C2C12 skeletal myotubes (2015)
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  • Journal Title: J Nutr Sci Vitanol Volume: in press
  • NAID: 130005074121
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• [Journal Article] Prevention of skeletal muscle atrophy in vitro using anti-ubiquitination oligopeptide carried by atelocollagen (2015)
  • Author(s): Kawai N, Hirasaka K, Maeda T, Haruna M, Shiota C, Ochi A, Abe T, Kohno S, Ohno A, Teshima-Kondo S Mori H, Tanaka E, Nikawa T
  • Journal Title: Biochim Biophys Acta Molecular Cell Research Volume: 1853 Issue: 5 Pages: 873-880
  • DOI: 10.1016/j.bbamcr.2015.01.024
  • Peer Reviewed / Open Access
• [Journal Article] N-Myristoylated ubiquitin ligase Cbl-b inhibitor prevents on glucocorticoid-induced atrophy in mouse skeletal muscle. (2015)
  • Author(s): Ochi A, Abe T, Nakao R, Yamamoto Y, Kitahata K, Takagi M, Hirasaka K, Ohno A, Teshima-Kondo S, Taesik G, Choi I, Kawamura T, Nemoto H, Mukai R, Terao J, Nikawa T.
  • Journal Title: Arch Biochem Biophys Volume: 570 Pages: 23-31
  • DOI: 10.1016/j.abb.2015.02.006
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• [Journal Article] A novel myogenic function residing in the 5’ non-coding region of Insulin receptor substrate-1 (Irs-1) transcript. (2015)
  • Author(s): Nagano H, Yamagishi N, Tomida C, Yano C, Aibara K, Kohno S, Abe T, Ohno A, Hirasaka K, Okumura Y, Mills EM, Nikawa T, Teshima-Kondo S.
  • Journal Title: BMC Cell Biol Volume: in press Issue: 1 Pages: 1-10
  • DOI: 10.1186/s12860-015-0054-8
  • NAID: 120006859993
  • Peer Reviewed / Open Access
• [Journal Article] Chronic exposure of VEGF inhibitors promotes the malignant phenotype of colorectal cancer cells (2015)
  • Author(s): Tomida C, Yamagishi N, Aibara K, Yano C, Uchida T, Abe T, Ohno A, Hirasaka K, Nikawa T, Teshima-Kondo S.
  • Journal Title: The Journal of Medical Investigation Volume: 62 Issue: 1.2 Pages: 75-79
  • DOI: 10.2152/jmi.62.75
  • NAID: 130005129700
  • ISSN: 1343-1420, 1349-6867
  • Peer Reviewed / Open Access
• [Journal Article] Effects of dietary soy protein on skeletal muscle volume and strength in humans with various physical activities. (2015)
  • Author(s): Hashimoto R, Sakai A, Murayama M, Ochi A, Abe T, Hirasaka K, Ohno A, Teshima-Kondo S, Yanagawa H, Yasui N, Inatsugi M, Doi D, Takeda K, Mukai R, Terao J, Nikawa T.
  • Journal Title: J Med Invest Volume: in press
  • NAID: 130005099151
  • Peer Reviewed
• [Journal Article] A novel CD3-specific antibody induces immunosuppression via impaired phosphorylation of LAT and PLCγ1 following T-cell stimulation (2014)
  • Author(s): Shiheido H, Aoyama T, Takahashi H, Hanaoka K, Abe T, Nishida E, Chen C, Koga O, Hikida M, Shibagaki Y, Morita A, Nikawa T, Hattori S, Watanabe T, Shimizu J.
  • Journal Title: Eur J Immunol Volume: in press Issue: 6 Pages: 1770-1780
  • DOI: 10.1002/eji.201344146
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• [Journal Article] Ubiquitin ligase Cbl-b and obesity-induced insulin resistance (2014)
  • Author(s): Abe T, Hirasaka K, Kohno S, Ochi A, Yamagishi N, Ohno A, Teshima-Kondo S, Nikawa T.
  • Journal Title: Endocr J, Volume: 61 Pages: 529-538
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• [Journal Article] Ubiquitin ligase Cbl-b and obesity-induced insulin resistance. (2014)
  • Author(s): Abe T, Hirasaka K, Kohno S, Ochi A, Yamagishi N, Ohno A, Teshima-Kondo S, Nikawa T.
  • Journal Title: Endocr J Volume: -
  • Peer Reviewed
• [Journal Article] Inhibition of C2C12 myotube atrophy by a novel HSP70 inducer, celastrol, via activation of Akt1 and ERK1/2 pathways. (2013)
  • Author(s): Gwag T, Park K, Kim E, Son C, Park J, Nikawa T, Choi I.
  • Journal Title: Arch Biochem Biophys Volume: 537 Issue: 1 Pages: 21-30
  • DOI: 10.1016/j.abb.2013.06.006
  • Peer Reviewed
• [Journal Article] Cbl-b Is a Critical Regulator of Macrophage Activation Associated With Obesity-Induced Insulin Resistance in Mice (2013)
  • Author(s): Abe T, Nikawa T, et al
  • Journal Title: Diabetes Volume: 62(6) Issue: 6 Pages: 1957-1969
  • DOI: 10.2337/db12-0677
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• [Journal Article] Chronic inhibition of tumor cell-derived VEGF enhances the malignant phenotype of colorectal cancer cells. (2013)
  • Author(s): Yamagishi N, Teshima-Kondo S, Masuda K, Nishida K, Kuwano Y, Dang DT, Dang LH, Nikawa T, Rokutan K.
  • Journal Title: BMC Cancer Volume: 13 Issue: 1 Pages: 229-229
  • DOI: 10.1186/1471-2407-13-229
  • Peer Reviewed
• [Journal Article] Isoflavones derived from soy beans prevent MuRF1-mediated muscle atrophy in C2C12 myotubes through SIRT1 activation (2013)
  • Author(s): Hirasaka K, et al.
  • Journal Title: J Nutr Sci Vitamin Volume: 59(印刷中)
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• [Journal Article] Refeeding with a standard diet after a 48-h fast elicits an inflammatory response in the mouse liver (2013)
  • Author(s): Oarada M, Miki T, Kohno S, Sakai K, Nikawa T, Yoneyama M, Gonoi T.
  • Journal Title: J Nutr Biochem Volume: (in press) Issue: 7 Pages: 1314-1323
  • DOI: 10.1016/j.jnutbio.2012.10.006
  • Peer Reviewed
• [Journal Article] Soy Glycinin Contains a Functional Inhibitory Sequence against Muscle Atrophy -Associated Ubiquitin Ligase Cbl-b (2013)
  • Author(s): Abe T, Kohno S, Yama T, Ochi A, Suto T, Hirasaka K, Ohno A, Teshima-Kondo S, Okumura Y, Oarada M, Choi I, Mukai R, Terao J, Nikawa T
  • Journal Title: Int J Endocrinol Volume: 2013 Pages: 907565-907565
  • DOI: 10.1155/2013/907565
  • Peer Reviewed
• [Journal Article] An intracellular fragment of osteoactivin formed by ectodomain shedding translocated to the nucleoplasm and bound to RNA binding proteins (2012)
  • Author(s): Utsunomiya K, et al.
  • Journal Title: Biosci Biotechnol Biochem Volume: 76 Pages: 2225-2229
  • Peer Reviewed
• [Journal Article] Prevention of disusemuscle atrophy by dietary ingestion of 8-prenylnaringenin in denervated mice (2012)
  • Author(s): Mukai R., Horikawa H., Fujikura Y., Kawamura T., Nemoto H., Nikawa T.
  • Journal Title: PLoS ONE Volume: 9 Issue: 9 Pages: e45048-e45048
  • DOI: 10.1371/journal.pone.0045048
  • Peer Reviewed
• [Journal Article] The potential of GPNMB as novel neuroprotective factor in amyotrophic lateral sclerosis. (2012)
  • Author(s): Tanaka H.. Shimazawa M., Kimura M., Takata M., Tsuruma K, Yamada M., Takahashi H., Hozumi I., Niwa J., Iguchi Y., Nikawa T., Sobue G., Inuzuka T. and Hara H.
  • Journal Title: Scientific Reports Volume: 2 Issue: 1 Pages: 573-573
  • DOI: 10.1038/srep00573
  • Peer Reviewed
• [Journal Article] Angiogenesis and myogenesis in mouse tibialis anterior muscles during distraction osteogenesis: VEGF, its receptors, and myogenin genes expression (2012)
  • Author(s): Nishisho T, Nikawa T, et al
  • Journal Title: J Orthop Res Volume: 30(11) Issue: 11 Pages: 1767-1773
  • DOI: 10.1002/jor.22136
  • Peer Reviewed
• [Journal Article] Unloading stress disturbs muscle regeneration through perturbed recruitment and function of macrophages. (2012)
  • Author(s): Kohno S, Nikawa T, et al
  • Journal Title: J Appl Physiol Volume: 112(10) Issue: 10 Pages: 1773-1782
  • DOI: 10.1152/japplphysiol.00103.2012
  • Peer Reviewed
• [Journal Article] Mitochondrial respiratory uncoupling promotes keratinocyte differentiation and blocks skin carcinogenesis (2012)
  • Author(s): Lago CU, et al.
  • Journal Title: Oncogene Volume: 31 Issue: 44 Pages: 4725-2731
  • DOI: 10.1038/onc.2011.630
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• [Journal Article] Refeeding with a high-protein diet after a 48 h fast causes acute hepatocellular injury in mice (2011)
  • Author(s): Motoko Oarada
  • Journal Title: British Journal of Nutrition Volume: 107 Issue: 10 Pages: 1435-1444
  • DOI: 10.1017/s0007114511004521
  • Peer Reviewed
• [Presentation] 無重力環境での筋蛋白質代謝と栄養 (2014)
  • Author(s): 二川健
  • Organizer: 第61回日本栄養改善学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県、横浜市）
  • Year and Date: 2014-08-20 – 2014-08-22
  • Invited
• [Presentation] 無重力や加齢による筋萎縮とユビキチンリガーゼ (2014)
  • Author(s): 二川健
  • Organizer: 第14回日本抗加齢医学会総会
  • Place of Presentation: 大阪国際会議場（大阪府、大阪市）
  • Year and Date: 2014-06-07 – 2014-06-08
  • Invited
• [Presentation] 廃用性筋萎縮とサルコぺニアの分子メカニズム：筋ユビキチンリガーゼの役割 (2014)
  • Author(s): 二川健
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡国際会議場（福岡県、福岡市）
  • Year and Date: 2014-05-21 – 2014-05-24
  • Invited
• [Presentation] Ubiquitin ligase Cbl-b is a negative regulator for insulin-like growth factor 1 signaling during muscle atrophy caused by unloading (2014)
  • Author(s): 二川健
  • Organizer: International Symposium on Mechanobiology 2014
  • Place of Presentation: Junko Fukutake Hall,Okayama University(岡山県、岡山市）
  • Year and Date: 2014-05-20 – 2014-05-23
  • Invited
• [Presentation] Unloading-mediated signal transduction in skeletal muscle. (2013)
  • Author(s): 二川健、安倍知紀、内田貴之、下田一花、越智ありさ、中尾玲子、真板綾子、平坂勝也、近藤茂忠、武田伸一
  • Organizer: 平成25年度 筋ジストロフィー 研究班会議
  • Place of Presentation: JA共済ビル カンファレンスホール（東京都）
• [Presentation] 廃用性筋萎縮改善ペプチド (2013)
  • Author(s): 二川健
  • Organizer: 第67回 日本栄養・食糧学会大会
  • Place of Presentation: 名古屋大学 豊田講堂（愛知県）
  • Invited
• [Presentation] 廃用性筋萎縮のメカニズムから見た加齢性機能低下(サルコペニア)との接点 (2012)
  • Author(s): 二川 健
  • Organizer: 日本麻酔科学会北海道・東北支部第2回学術集会
  • Place of Presentation: 札幌コンベンションセンター(北海道)(招待講演)
  • Year and Date: 2012-09-01
• [Presentation] Muscle regeneration during unloading (2012)
  • Author(s): 二川 健
  • Organizer: 9th Korea-Japan Joint Semimar on Space Environment Utilization Research
  • Place of Presentation: つくば宇宙センター(茨城県)
• [Book] 薬事日報「寝たきりや無重力による筋萎縮とユビキチンリガーゼ」 (2015)
  • Author(s): 北畑香菜子、越智ありさ、二川健
  • Total Pages: 24
  • Publisher: 薬事日報社
• [Book] 生化学「Skeletal muscle atrophy and amino acidskeletal muscle atrophy and amino acid」 (2014)
  • Author(s): Ochi A, Kitahata K, Nikawa T
  • Total Pages: 422
  • Publisher: 生化学学会
• [Book] 「メカノバイオロジー」機械的ストレスと筋萎縮/筋肥大 (2013)
  • Author(s): 二川 健
  • Publisher: 化学同人(印刷中)
• [Remarks] 徳島大学 医学部 医科栄養学科 生体栄養学分野
  • URL: http://www.tokushima-u.ac.jp/med/culture/seitaieiyou/
• [Remarks]
  • URL: http://www.tokushima-u.ac.jp/med/culture/seitaieiyou/
• [Patent(Industrial Property Rights)] 筋萎縮抑制剤 (2015)
  • Inventor(s): 二川 健、川島恵利子
  • Industrial Property Rights Holder: 徳島大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-531566
  • Filing Date: 2015-02-16
• [Patent(Industrial Property Rights)] 筋萎縮抑制剤 (2012)
  • Inventor(s): 二川健
  • Industrial Property Rights Holder: JNC 徳島大学
  • Filing Date: 2012-08-24
  • Overseas