Molecular rehabilitation of mitochondrial function towards preventing muscle atrophy

• Project/Area Number: 15H04960
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: The University of Tokushima
• Principal Investigator: NIKAWA Takeshi 徳島大学, 大学院医歯薬学研究部(医学系), 教授 (20263824)
• Co-Investigator(Kenkyū-buntansha): 曽我部 正博 名古屋大学, 医学系研究科, 特任教授 (10093428) ; 鈴木 穣 東京大学, 大学院新領域創成科学研究科, 教授 (40323646) ; 宮本 賢一 徳島大学, 大学院医歯薬学研究部(医学系), 教授 (70174208)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2017: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2015: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000)
• Keywords: 筋萎縮 / ミトコンドリア / 酸化ストレス / 抗酸化栄養素 / ユビキチンリガーゼCbl-b / 転写因子Egr / 筋拘縮 / 分子リハビリテーション / 遅筋の速筋化 / Egr / アコニターゼ / 国際宇宙ステーション / メカノセンシング / ミトコンドリア酵素 / オルガネラ相関 / Mitofusin-2 / メカノセンサー / カルシウムシグナリング

Outline of Final Research Achievements

"Bedridden" not only reduces the quality of life for the elderly, it causes an excessive burden on caregivers and a sharp increase in social security expenses. The cause of this bedridden is muscle atrophy / contracture. In collaboration with JAXA (Japan Aerospace Exploration Agency), we need to restore the function of mitochondria, a mechanosensor, to prevent atrophy and contracture of muscles. Continuing from the last fiscal year, this study demonstrates the effectiveness of a new rehabilitation method to elucidate the mechanism of muscle atrophy and muscle contracture caused by Unloading, such as weightlessness and bedridden, and intake of functional ingredients enabling mitochondrial function recovery did.

Research Products

• [Int'l Joint Research] フランス国立科学研究センター(フランス)
• [Int'l Joint Research] テキサス大学、オースチン校/NASA(米国)
• [Int'l Joint Research] Yonsei大学(韓国)
• [Journal Article] VEGF pathway-targeting drugs induce evasive adaptation by activation of neuropilin-1/cMet in colon cancer cells (2018)
  • Author(s): Tomida Chisato、Yamagishi Naoko、Nagano Hikaru、Uchida Takayuki、Ohno Ayako、Hirasaka Katsuya、Nikawa Takeshi、Teshima-Kondo Shigetada
  • Journal Title: International Journal of Oncology Volume: 52 Pages: 1350-1362
  • DOI: 10.3892/ijo.2018.4291
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Distinct Gene Expression Profile Distinguishes Increased Metabolic Activity in Spontaneously Hyperactive Rats While Sedentary from That Induced by Exercise (2018)
  • Author(s): Abe Manami、Matsuo Yuki、Harada-Sukeno Akiko、Uchida Takayuki、Kitahata Kanako、Tomida Chisato、Hirasaka Katsuya、Teshima-Kondo Shigetada、Harada Nagakatsu、Nakaya Yutaka、Sakaue Hiroshi、Nakao Reiko、Nikawa Takeshi
  • Journal Title: Advances in Biological Chemistry Volume: 08 Issue: 01 Pages: 1-14
  • DOI: 10.4236/abc.2018.81001
  • Peer Reviewed
• [Journal Article] Reactive oxygen species up-regulate expression of muscle atrophy-associated ubiquitin ligase Cbl-b in rat L6 skeletal muscle cells. (2018)
  • Author(s): Uchida T, Sakashita Y, Kitahata K, Yamashita Y, Tomida C, Kimori Y, Komatsu A, Hirasaka K, Ohno A, Nakao R, Higashitani A, Higashibata A, Ishioka N, Shimazu T, Kobayashi T, Okumura Y, Choi I, Oarada M, Mills EM, Teshima-Kondo S, Takeda S, Tanaka E, Tanaka K, Sokabe M, Nikawa T.
  • Journal Title: Am J Physiol Cell Physiol Volume: 印刷中
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• [Journal Article] Co-Administration of Myostatin-Targeting siRNA and ActRIIB-Fc Fusion Protein Increases Masseter Muscle Mass and Fiber Size (2017)
  • Author(s): BAYARSAIKHAN Od、KAWAI Nobuhiko、MORI Hiroyo、KINOUCHI Nao、NIKAWA Takeshi、TANAKA Eiji
  • Journal Title: Journal of Nutritional Science and Vitaminology Volume: 63 Issue: 4 Pages: 244-248
  • DOI: 10.3177/jnsv.63.244
  • NAID: 130007314434
  • ISSN: 0301-4800, 1881-7742
  • Peer Reviewed / Open Access
• [Journal Article] Update on recent progress in vitamin D research. Vitamin D and muscle tissues (2017)
  • Author(s): Kaneko I, Miyamoto KI, Nikawa T
  • Journal Title: Clin Calcium Volume: 27 Pages: 1571-1578
• [Journal Article] Regorafenib induces adaptive resistance of colorectal cancer cells via inhibition of vascular endothelial growth factor receptor (2017)
  • Author(s): Tomida Chisato、Nagano Hikaru、Yamagishi Naoko、Uchida Takayuki、Ohno Ayako、Hirasaka Katsuya、Nikawa Takeshi、Teshima-Kondo Shigetada
  • Journal Title: The Journal of Medical Investigation Volume: 64 Issue: 3.4 Pages: 262-265
  • DOI: 10.2152/jmi.64.262
  • NAID: 130006105177
  • ISSN: 1343-1420, 1349-6867
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• [Journal Article] Antiangiogenic agent sunitinib induces epithelial to mesenchymal transition and accelerates motility of colorectal cancer cells (2017)
  • Author(s): Chisato Tomida, Naoko Yamagishi, Hikaru Nagano, Takayuki Uchida, Ayako Ohno, Katsuya Hirasaka, Takeshi Nikawa, Shigetada Teshima-Kondo
  • Journal Title: The Journal of Medical Investigation Volume: 64 Issue: 3.4 Pages: 250-254
  • DOI: 10.2152/jmi.64.250
  • NAID: 130006105181
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• [Journal Article] Nutritional counseling regulates interdialytic weight gain and blood pressure in outpatients receiving maintenance hemodialysis (2017)
  • Author(s): Sakai A, Hamada H, Hara K, Mori K, Uchida T, Mizuguchi T, Minaguchi J, Shima K, Kawashima S, Hamada Y, Nikawa T*.
  • Journal Title: J Med Invest Volume: 64 Pages: 129-135
  • Peer Reviewed / Open Access
• [Journal Article] Development and performance evaluation of a three-dimensional clinostat synchronized heavy-ion irradiation system (2017)
  • Author(s): Ikeda H, Hidema J and Takahashi A et al.
  • Journal Title: Life Sci Space Res Volume: 12 Pages: 51-60
  • DOI: 10.1016/j.lssr.2017.01.003
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Modulation of cutaneous extracellular collagen contraction by phosphorylation status of p130Cas (2017)
  • Author(s): Takeya M, Okumura Y, Nikawa T*
  • Journal Title: J Physiol Sci Volume: 印刷中
  • NAID: 40021302104
  • Peer Reviewed
• [Journal Article] Metabolic Suppression by 3-Iodothyronamine Induced Muscle Cell Atrophy <i>via</i> Activation of FoxO–Proteasome Signaling and Downregulation of Akt1–S6K Signaling (2017)
  • Author(s): Ju H, Kim T, Chung CM, Park J, Nikawa T, Park K, Choi I*
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 40 Issue: 5 Pages: 576-582
  • DOI: 10.1248/bpb.b16-00653
  • NAID: 130005631971
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Distinct effects of dietary whey peptide and soy protein on denervation-mediated muscle atrophy. (2017)
  • Author(s): Takagi M, Uchida T, Takatsu E, Kishimoto H, Ida K, Ishida Y, Ono-Ohmachi A, Morita Y, Kato K, Ochi A, Ohno-Maita A, Oarada M, Abe T, Teshima-Kondo S, Nakao R, Hirasaka K, Nikawa T*.
  • Journal Title: J Nutr Food Sci Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] 8-Prenylnaringenin promotes recovery from immobilization-induced disuse muscle atrophy through activation of the Akt phosphorylation pathway in mice (2016)
  • Author(s): Mukai R, Horikawa H, Lin PY, Tsukumo N, Nikawa T, Kawamura T, Nemoto H, Terao J*
  • Journal Title: Am J Physiol Regul Integr Comp Physiol Volume: 311 Issue: 6 Pages: 1022-1031
  • DOI: 10.1152/ajpregu.00521.2015
  • NAID: 120006535072
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Dietary Supplementation with Isoflavones Prevents Muscle Wasting in Tumor-Bearing Mice (2016)
  • Author(s): Hirasaka K*, Saito S, Yamaguchi S, Miyazaki R, Wang Y, Haruna M, Taniyama S, Higashitani A, Terao J, Nikawa T, Tachibana K
  • Journal Title: Journal of Nutritional Science and Vitaminology Volume: 62 Issue: 3 Pages: 178-184
  • DOI: 10.3177/jnsv.62.178
  • NAID: 130005253104
  • ISSN: 0301-4800, 1881-7742
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Preventive effect of dietary quercetin on disuse muscle atrophy by targeting mitochondria in denervated mice (2016)
  • Author(s): Mukai R, Matsui N, Fujikura Y, Matsumoto N, Hou DX, Kanzaki N, Shibata H, Horikawa M, Iwasa K, Hirasaka K, Nikawa T, Terao J
  • Journal Title: J Nutr Biochem Volume: 31 Pages: 67-76
  • DOI: 10.1016/j.jnutbio.2016.02.001
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Capric Acid Up-Regulates UCP3 Expression without PDK4 Induction in Mouse C2C12 Myotubes (2016)
  • Author(s): Abe T, Hirasaka K, Kohno S, Tomida C, Haruna M, Uchida T, Ohno A, Oarada M, Teshima-Kondo S, Okumura Y, Choi I, Aoyama T, Terao J, Nikawa T*.
  • Journal Title: Journal of Nutritional Science and Vitaminology Volume: 62 Issue: 1 Pages: 32-39
  • DOI: 10.3177/jnsv.62.32
  • NAID: 130005148603
  • ISSN: 0301-4800, 1881-7742
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] UCP3 is associated with Hax-1 in mitochondria in the presence of calcium ion (2016)
  • Author(s): Hirasaka K, Mills EM, Haruna M, Bando A, Ikeda C, Abe T, Kohno S, Nowinski SM, Lago CU, Akagi K, Tochio H, Ohno A, Teshima-Kondo S, Okumura Y, Nikawa T
  • Journal Title: Biochem Biophys Res Commun Volume: 472 Issue: 1 Pages: 108-113
  • DOI: 10.1016/j.bbrc.2016.02.075
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Structural analysis of the TKB domain of ubiquitin ligase Cbl-b complexed with its small inhibitory peptide, Cblin (2016)
  • Author(s): Ohno A, Ochi A, Maita N, Ueji T, Bando A, Nakao R, Hirasaka K, Abe T, Teshima-Kondo S, Nemoto H, Okumura Y, Higashibata A, Yano S, Tochio H, Nikawa T
  • Journal Title: Arch Biochem Biophys Volume: 594 Pages: 1-7
  • DOI: 10.1016/j.abb.2016.02.014
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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: 32 Issue: 4 Pages: 486-96
  • DOI: 10.3109/07420528.2014.1003350
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Refeeding with glucose rather than fructose elicits greater hepatic inflammatory gene expression in mice (2015)
  • Author(s): Oarada M, et al.
  • Journal Title: Nutrition Volume: 31 Issue: 5 Pages: 757-65
  • DOI: 10.1016/j.nut.2014.11.014
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Celastrol overcomes HSP72 gene silencing-mediated muscle atrophy and induces myofiber preservation. (2015)
  • Author(s): Gwag T, Park K, Park J, Lee JH, Nikawa T, Choi I.
  • Journal Title: J Physiol Pharmacol. Volume: 66 Pages: 273-283
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Flavones Inhibit LPS-Induced Atrogin-1/MAFbx Expression in Mouse C2C12 Skeletal Myotubes (2015)
  • Author(s): Shiota C, Abe T, Kawai N, Ohno A, Teshima-Kondo S, Mori H, Terao J, Tanaka E, Nikawa T
  • Journal Title: J Nutr Sci Vitaminol (Tokyo) Volume: 61 Issue: 2 Pages: 188-194
  • DOI: 10.3177/jnsv.61.188
  • NAID: 130005074121
  • Peer Reviewed
• [Journal Article] The malignant progression effects of regorafenib in human colon cancer cells (2015)
  • Author(s): Tomida C, Aibara K, Yamagishi N, Yano C, Nagano H, Abe T, Ohno A, Hirasaka K, Nikawa T, Teshima-Kondo S
  • Journal Title: The Journal of Medical Investigation Volume: 62 Issue: 3.4 Pages: 195-198
  • DOI: 10.2152/jmi.62.195
  • NAID: 130005099146
  • ISSN: 1343-1420, 1349-6867
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mitochondrial uncoupling links lipid catabolism to Akt inhibition and resistance to tumorigenesis. (2015)
  • Author(s): Nowinski SM, Solmonson A, Rundhaug JE, Rho O, Cho J, Lago CU, Riley CL, Lee S, Kohno S, Dao CK, Nikawa T, Bratton SB, Wright CW, Fischer SM, DiGiovanni J, Mills EM.
  • Journal Title: Nat Commun. Volume: 6 Issue: 1 Pages: 8137-8137
  • DOI: 10.1038/ncomms9137
  • NAID: 120006999408
  • Peer Reviewed / Int'l Joint Research
• [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 M, Mukai R, Terao J, Nikawa T
  • Journal Title: The Journal of Medical Investigation Volume: 62 Issue: 3.4 Pages: 177-183
  • DOI: 10.2152/jmi.62.177
  • NAID: 130005099151
  • ISSN: 1343-1420, 1349-6867
  • Peer Reviewed / Open Access
• [Presentation] Molecular mechanism and nutritional approach for unloading-mediated muscle atrophy (2018)
  • Author(s): Takeshi Nikawa, Takayuki Uchida, Ayako Miata (Ohno), Reiko Nakao
  • Organizer: 2018 International Conference on Functional Food for improving Sarcopenia, Cachexia and Frailty
  • Int'l Joint Research / Invited
• [Presentation] Unloading induces reactive oxygen species associated signal transduction toward atrophy in skeletal muscle cells (2017)
  • Author(s): Takeshi Nikawa
  • Organizer: 3rd Internation Symposium on Mechanobiology
  • Int'l Joint Research / Invited
• [Presentation] 無重力ストレスに対する初期応答酵素（アコニターゼ）の筋萎縮における役割 (2017)
  • Author(s): 二川健
  • Organizer: 2017年度生命科学系学会合同年次大会第40回日本分子生物学会年会、第90回日本生化学会大会
• [Presentation] Molecular mechanism of microgravity-induced muscle atrophy (2017)
  • Author(s): 二川健
  • Organizer: 第65回国際歯科研究学会日本部会総会・学術大会
  • Invited
• [Presentation] Unloading induces reactive oxygen species associated signal transduction toward atrophy in skeletal muscle cells (2017)
  • Author(s): Takeshi Nikawa
  • Organizer: 14th Japan-Korea Joint Seminar on Space Environment Utilization Research
  • Int'l Joint Research
• [Presentation] 無重力ストレスによる筋萎縮における酸化ストレスの重要性 (2017)
  • Author(s): 内田貴之、真板綾子、中尾玲子、小林剛、東谷篤志、石原直忠、武田伸一、曽我部正博、二川健
  • Organizer: 日本筋学会第3回学術集会
• [Presentation] 無重力による酸化ストレス産生を介した筋細胞内シグナル・トランスダクション (2017)
  • Author(s): 内田貴之、木森有希、二宮みゆき、坂下禎宏、安倍知紀、真板綾子、中尾玲子、平坂勝也、東谷篤志、小林剛、曽我部正博、武田伸一、二川健
  • Organizer: 第71回日本栄養・食糧学会大会
• [Presentation] 筋蛋白質代謝改善のための栄養学的アプローチ (2016)
  • Author(s): 二川健
  • Organizer: 第2回日本筋学会学術集会
  • Place of Presentation: 国立精神・神経医療研究センター（東京都・小平市）
  • Year and Date: 2016-08-05
  • Invited
• [Presentation] Effects of dietary soy protein on skeletal muscle volume and strength in humans with various physical activities (2016)
  • Author(s): Takeshi Nikawa, Rie Hashimoto, Katsuya Hirasaka, Chiaki Yano, Kana Aibara, Ayako Ohno(maita), Kazuhito Akama
  • Organizer: Molecular Mechanisms Modulating Skeletal Muscle Development and Homeostasis in Health and Disease
  • Place of Presentation: Pacific Grove（アメリカ）
  • Year and Date: 2016-06-07
  • Int'l Joint Research
• [Presentation] 寝たきりや無重力による筋萎縮のメカニズム解明とその栄養学的治療法の開発 (2016)
  • Author(s): 二川健
  • Organizer: 第70回日本栄養・食糧学会大会
  • Place of Presentation: 神戸国際会議場（兵庫県・神戸市）
  • Year and Date: 2016-05-13
  • Invited
• [Presentation] 廃用性筋萎縮改善ペプチド (2016)
  • Author(s): 二川健、赤間一仁
  • Organizer: 日本農芸化学会2016年度大会
  • Place of Presentation: 札幌コンベンションセンター（北海道・札幌市）
  • Year and Date: 2016-03-27
  • Invited
• [Presentation] Unloadingストレスによる筋細胞内シグナル・トランスダクション (2016)
  • Author(s): 二川健
  • Organizer: 第34回日本骨代謝学会学術集会／第3回アジア太平洋骨代謝学会議
  • Place of Presentation: 大阪国際会議場（大阪府・大阪市）
  • Invited
• [Presentation] Microgravity-induced signal transduction in skeletal muscle cells (2016)
  • Author(s): Takeshi Nikawa
  • Organizer: The 27th International Conference on Magnetic Resonance in Biological Systems
  • Place of Presentation: 北海道大学（北海道・札幌市）
  • Int'l Joint Research / Invited
• [Presentation] 筋萎縮を予防・治療できる新規機能性食材の開発 (2015)
  • Author(s): 二川健
  • Organizer: 第7回「栄養とエイジング」国際会議プログラム
  • Place of Presentation: 東京大学弥生講堂（東京都・文京区）
  • Year and Date: 2015-09-29
  • Int'l Joint Research / Invited
• [Presentation] Novel nutritional approarches against skeletal muscle atrophy: From proteolysis to oxdative stress (2015)
  • Author(s): 二川健
  • Organizer: International Symposium on Dietary Antioxidants and Oxidative Stress in Health
  • Place of Presentation: 淡路夢舞台国際会議場（兵庫県・淡路市）
  • Year and Date: 2015-08-30
  • Int'l Joint Research / Invited
• [Presentation] ビタミンDと筋肉 (2015)
  • Author(s): 二川健
  • Organizer: 第1回Neo Vitamin D Workshop学術集会
  • Place of Presentation: 大津プリンスホテル（滋賀県・大津市）
  • Year and Date: 2015-08-28
  • Invited
• [Presentation] 廃用性筋萎縮の分子メカニズムとその栄養学的治療法の開発 (2015)
  • Author(s): 二川健
  • Organizer: 日本食品科学工学会第62回大会
  • Place of Presentation: 京都大学（京都府・京都市）
  • Year and Date: 2015-08-27
  • Invited
• [Presentation] Unloading-mediated signal transduction in skeletal muscle cells (2015)
  • Author(s): 二川健
  • Organizer: 12th Meeting of Bone Biology Forum
  • Place of Presentation: クロス・ウェーブ幕張（千葉県・千葉市）
  • Year and Date: 2015-08-21
  • Invited
• [Presentation] 筋萎縮の分子メカニズムとその栄養学的治療法 (2015)
  • Author(s): 二川健
  • Organizer: 日本アミノ酸学会 第６回夏のシンポジウム
  • Place of Presentation: 阿波観光ホテル（徳島県・徳島市）
  • Year and Date: 2015-07-18
  • Invited
• [Book] Clinical Calcium, 筋肉研究の最前線 (2017)
  • Author(s): 岸本ひかる、内田貴之、北畑香菜子、二川健
  • Total Pages: 144
  • Publisher: 医薬ジャーナル社
• [Book] Clinical Calcium, 運動・スポーツと骨・関節 (2017)
  • Author(s): 坂下禎宏、内田貴之、二川健
  • Total Pages: 172
  • Publisher: 医薬ジャーナル社
• [Book] 三訂 基礎栄養学 (2015)
  • Author(s): 塚原典子、二川健、近藤茂忠、松田早苗、山本孝史、薗田勝、安倍知紀
  • Total Pages: 205
  • Publisher: 建帛社