The role of mitoNEET on the regulation of mitochondrial function in skeletal muscle failure

• Project/Area Number: 26350879
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied health science
• Research Institution: Hokkaido University
• Principal Investigator: Kinugawa Shintaro 北海道大学, 医学研究科, 講師 (60399871)
• Co-Investigator(Kenkyū-buntansha): 筒井 裕之 九州大学, 医学研究院, 教授 (70264017) ; 松島 将士 九州大学, 大学病院, 助教 (80552869) ; 横田 卓 北海道大学, 医学研究科, 助教 (90374321)
• Research Collaborator: FURIHATA Takaaki ; TAKADA Shingo
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: ミトコンドリア / 骨格筋不全 / 鉄代謝

Outline of Final Research Achievements

In various chronic disease model mice, exercise capacity was reduced, skeletal muscle abnormalities such as mitochondrial dysfunction in the skeletal muscle and fiber type switch occurred, iron content within mitochondria was increased, and oxidative stress was enhanced. In mice deleted mitoNEET, we newly created, iron content within mitochondria was increased, oxidative stress was enhanced, and mitochondrial morphology and function was impaired, which resulted in the reduced exercise capacity. There were no differences in the known protein associated with iron homeostasis in mitochondria. In the analysis by protein interaction, we found that mitoNEET combined with cytosolic protein X associated with iron homeostasis and mitochondrial inner membrane protein Y associated with transportation of some substances into mitochondria.

Research Products

• [Journal Article] The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes. (2016)
  • Author(s): Mizushima, W., Takahashi , H., Watanabe, M., Kinugawa, S., Matsushima, S., Takada, S., Yokota, T., Furihata, T., Matsumoto, J., Tsuda, M., Chiba, I., Nagashima, S., Yanagi, S., Matsumoto, M., Nakayama, K.I., Tsutsui, H. and Hatakeyama, S.
  • Journal Title: J. Mol. Cell. Cardiol. Volume: 100 Pages: 43-53
  • DOI: 10.1016/j.yjmcc.2016.09.013
  • NAID: 120006360069
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling. (2016)
  • Author(s): Matsushima S, Kuroda J, Zhai P, Liu T, Ikeda S, Nagarajan N, Oka S, Yokota T, Kinugawa S, Hsu C, Li H , Tsutsui H, Sadoshima J.
  • Journal Title: Journal of Clinical Investigation Volume: 126 Issue: 9 Pages: 3403-3416
  • DOI: 10.1172/jci85624
  • NAID: 120006809287
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Dipeptidyl peptidase-4 inhibitor improved exercise capacity and mitochondrial biogenesis in mice with heart failure via activation of GLP-1 receptor signaling. (2016)
  • Author(s): Takada S, Masaki Y, Kinugawa S, Matsumoto J, Furihata T, Mizushima W, Kadoguchi T, Fukushima A, Homma T, Takahashi M, Harashima S, Matsushima S, Yokota T, Tanaka S, Okita K, Tsutsui H
  • Journal Title: Cardiovasc Res Volume: 111 Issue: 4 Pages: 338-347
  • DOI: 10.1093/cvr/cvw182
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Direct renin inhibitor ameliorated insulin resistance by improving insulin signaling and oxidative stress in the skeletal muscle from post-infarct heart failure in mice. (2016)
  • Author(s): Fukushima A, Kinugawa S, Takada S, Matsumoto J, Furihata T, Mizushima W, Tsuda M, Yokota T, Matsushima S, Okita K, Tsutsui H
  • Journal Title: Eur J Pharmacol Volume: 779 Pages: 147-156
  • DOI: 10.1016/j.ejphar.2016.03.022
  • NAID: 120006219992
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Skeletal Muscle Abnormalities in Heart Failure (2015)
  • Author(s): Kinugawa S, Takada S, Matsushima S, Okita K, Tsutsui H
  • Journal Title: International Heart Journal Volume: 56 Issue: 5 Pages: 475-484
  • DOI: 10.1536/ihj.15-108
  • NAID: 130005102118
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed / Open Access
• [Journal Article] Curcumin ameliorates skeletal muscle atrophy in type I diabetic mice via inhibiting the protein ubiqutination (2015)
  • Author(s): Ono T, Takada S, Kinugawa S, Tsutsui H
  • Journal Title: Exp Physiol Volume: 100 Issue: 9 Pages: 1052-1063
  • DOI: 10.1113/ep085049
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] AST-120 ameliorates lowered exercise capacity and mitochondrial biogenesis in the skeletal muscle from mice with chronic kidney disease via reducing oxidative stress. (2015)
  • Author(s): Nishikawa M, Ishimori N, Takada S, Saito A, Kadoguchi T, Furihata T, Fukushima A, Matsushima S, Yokota T, Kinugawa S, Tsutsui H
  • Journal Title: Nephrol Dial Transplant. Volume: in press Issue: 6 Pages: 182-188
  • DOI: 10.1093/ndt/gfv103
  • NAID: 120005743055
  • Peer Reviewed
• [Journal Article] Low-intensity exercise under ischemic conditions enhances metabolic stress in patients with heart failure (2015)
  • Author(s): Takahashi M, Kinugawa S, Takada S, Hirabayashi K, Yokota T, Matsushima S, Saito A, Okita K, Tsutsui H
  • Journal Title: Int J Cardiol Volume: 201 Pages: 142-4
  • DOI: 10.1016/j.ijcard.2015.08.022
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Serum brain-derived neurotrophic factor level predicts adverse clinical outcomes in patients with heart failure (2015)
  • Author(s): Fukushima A, Kinugawa S, Homma T, Masaki Y, Furihata T, Yokota T, Matsushima S, Takada S, Kadoguchi T, Oba K, Okita K, Tsutsui H
  • Journal Title: J Card Fail Volume: 21 Issue: 4 Pages: 300-306
  • DOI: 10.1016/j.cardfail.2015.01.003
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Angiotensin II can directly induce mitochondrial dysfunction, decrease oxidative fibre number and induce atrophy in mouse hindlimb skeletal muscle. (2015)
  • Author(s): Kadoguchi T, Kinugawa S, Takada S, Fukushima A, Furihata T, Homma T, Masaki Y, Mizushima W, Nishikawa M, Takahashi M, Yokota T, Matsushima S, Okita K, Tsutsui H
  • Journal Title: Exp Physiol Volume: 100 Issue: 3 Pages: 312-322
  • DOI: 10.1113/expphysiol.2014.084095
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Intramyocellular lipid is increased in the skeletal muscle of patients with dilated cardiomyopathy with lowered exercise capacity. (2014)
  • Author(s): Hirabayashi K, Kinugawa S, Yokota T, Takada S, Fukushima A, Suga T, Takahashi M, Ono T, Morita N, Omokawa M, Harada K, Oyama-Manabe N, Shirato H, Matsushima S, Okita K, Tsutsui H
  • Journal Title: International Journal of Cardiology Volume: 176 Issue: 3 Pages: 1110-1112
  • DOI: 10.1016/j.ijcard.2014.07.113
  • NAID: 120006809251
  • Peer Reviewed
• [Journal Article] (Pro)renin receptor in skeletal muscle is involved in the development of insulin resistance associated with postinfarct heart failure in mice (2014)
  • Author(s): Fukushima A, Kinugawa S, Takada S, Matsushima S, Sobirin MA, Ono T, Takahashi M, Suga T, Homma T, Masaki Y, Furihata T, Kadoguchi T, Yokota T, Okita K, Tsutsui H
  • Journal Title: American Journal of Physiology Endocrinology and Metabolism Volume: 307 Issue: 6 Pages: E503-E514
  • DOI: 10.1152/ajpendo.00449.2013
  • Peer Reviewed
• [Journal Article] Pioglitazone ameliorates the lowered exercise capacity and impaired mitochondrial function of the skeletal muscle in type 2 diabetic mice. (2014)
  • Author(s): Takada S, Hirabayashi K, Kinugawa S, Yokota T, Matsushima S, Suga T, Kadoguchi T, Fukushima A, Homma T, Mizushima W, Masaki Y, Furihata T, Katsuyama R, Okita K, Tsutsui H
  • Journal Title: European Journal of Pharmacology Volume: 740 Pages: 690-696
  • DOI: 10.1016/j.ejphar.2014.06.008
  • NAID: 120005476207
  • Peer Reviewed
• [Journal Article] Combination of exercise training and diet restriction normalizes limited exercise capacity and impaired skeletal muscle function in diet-induced diabetic mice. (2014)
  • Author(s): Suga T, Kinugawa S, Takada S, Kadoguchi T, Fukushima A, Homma T, Masaki Y, Furihata T, Takahashi M, Sobirin MA, Ono T, Hirabayashi K, Yokota T, Tanaka S, Okita K, Tsutsui H.
  • Journal Title: Endocrinology Volume: 155 Issue: 1 Pages: 68-80
  • DOI: 10.1210/en.2013-1382
  • Peer Reviewed
• [Presentation] Mitochondrial protein acetylation in skeletal muscle was associated with exercise intolerance in heart failure after myocardial infarction. (2016)
  • Author(s): Tsuda M, Kinugawa S, Takada S, Fukushima A, Yokota T, Mizushima W, Furihata T, Matsumoto J, Katayama T, Nakajima T, Maekawa S, Nambu H, Shirakawa R, Kakutani N, Okita K, Tsutsui H
  • Organizer: American Heart Association Scientific Session 2016.
  • Place of Presentation: New Orleans, USA
  • Int'l Joint Research
• [Presentation] Brain-derived neurotrophic factor plays an important role of exercise capacity and mitochondrial function in the skeletal muscle in mice with post-infarct heart failure. (2016)
  • Author(s): Nakajima T, Kinugawa S, Matsumoto J, Takada S, Furihata T, Tsuda M, Katayama T, Nambu H, Shirakawa R, Maekawa S, Kakutani N, Mizushima W, Yokota T, Okita K, Tsutsui H
  • Organizer: American Heart Association Scientific Session 2016.
  • Place of Presentation: New Orleans, USA
  • Int'l Joint Research
• [Presentation] The activation of glucagon-like peptide-1 improves the mitochondrial abnormalities in skeletal muscle and exercise intolerance in heart failure mice. (2016)
  • Author(s): Katayama T, Takada S, Masaki Y, Kinugawa S, Matsumoto J, Nakajima T, Tsuda M, Furihata T, Mizushima W, Fukushima A, Yokota T, Okita K, Tsutsui H
  • Organizer: American Heart Association Scientific Session 2016
  • Place of Presentation: New Orleans, USA
  • Int'l Joint Research
• [Presentation] Brain-derived neurotrophic factor improves exercise capacity and mitochondrial function in skeletal muscles of mice with heart failure via AMPK-PGC1α signaling. (2016)
  • Author(s): Matsumoto J, Takada S, Furihata T, Tsuda M, Nakajima T, Katayama T, Yokota T, Kinugawa S
  • Organizer: The 33rd Annual Meeting of the International Society for Heart Research Japanese Section
  • Place of Presentation: 東京コンベンションホール(東京都特別区)
  • Int'l Joint Research
• [Presentation] mitoNEET regulates mitochondrial iron contents in the heart (2016)
  • Author(s): Maekawa S, Furihata T, Takada S, Fukushima A, Tsuda M, Matsumoto J, Yokota T, Kinugawa S
  • Organizer: The 33rd Annual Meeting of the International Society for Heart Research Japanese Section
  • Place of Presentation: 東京コンベンションホール（東京都特別区)
  • Int'l Joint Research
• [Presentation] Mitochondral iron homeostatis in the heart (2016)
  • Author(s): 降旗高明，絹川真太郎
  • Organizer: 第２０回日本心不全学会学術集会
  • Place of Presentation: ロイトン札幌(札幌市)
  • Invited
• [Presentation] Desruption of mitoNEET, outer mitochondrial membrane protein, increases mitochondrial iron content in the heart (2015)
  • Author(s): Furihata T, Kinugawa S, Takada S, Matsushima S, Mizushima W, Yokota T, Tsutsui H
  • Organizer: Desruption of mitoNEET, outer mitochondrial membrane protein, increases mitochondrial iron content in the heart
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-12-11
  • Int'l Joint Research
• [Presentation] Decreased brain-derived neurotrophic factor impairs mitochondrial function via ampk-pgc1a signaling in the skeletal muscle from post-infarct heart failure mice (2015)
  • Author(s): Matsumoto J, Kinugawa S, Takada S, Furihata T, Mizushima W, Matsushima S, Yokota T, Tsutsui H
  • Organizer: The 32nd Annual Meeting of the International Society for Heart Research Japanese Section
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-12-11
  • Int'l Joint Research
• [Presentation] Brain-derived neurotrophic factor could regulate mitochondrial function in the skeletal muscle through ampk-pgc1a signaling in heart failure mice (2015)
  • Author(s): Matsumoto J, Kinugawa S, Takada S, Furihata T, Mizushima W, Tsuda M, Nakajima T, Katayama T, Fukuoka R, Yokota T, Matsushima S, Okita K, Tsutsui H
  • Organizer: American Heart Association Scientific Session 2015
  • Place of Presentation: Orlando（USA）
  • Year and Date: 2015-11-09
  • Int'l Joint Research
• [Presentation] Deletion of NAD(P)H oxidase 2 attenuates angiotensin II-induced skeletal muscle atrophy (2015)
  • Author(s): Mizushima W, Kinugawa S, Kadoguchi T, Takada S, Fukushima A, Furihata T, Matsumoto J, Tsuda M, Yokota T, Matsushima S, Okita K, Tsutsui H
  • Organizer: American Heart Association Scientific Session 2015
  • Place of Presentation: Orlando（USA）
  • Year and Date: 2015-11-09
  • Int'l Joint Research
• [Presentation] Recombinant human BDNF can mimic effects of exercise training in mice (2015)
  • Author(s): Takada S, Kinugawa S, Matsushima S, Yokota T, Mizushima W, Furihata T, Matsumoto J, Tsuda M, Fukushima A, Okita K, Tsutsui H
  • Organizer: American Heart Association Scientific Session 2015
  • Place of Presentation: Orlando（USA）
  • Year and Date: 2015-11-09
  • Int'l Joint Research
• [Presentation] Disruption of outer mitochondrial membrane protein, mitoNEET, increases mitochondrial iron content in the heart. (2014)
  • Author(s): Furihata T, Kinugawa S, Matsushima S, Takada S, Fukushima A, Mizushima W, Kadoguchi T, Masaki Y, Yokota T, Tsutsui H
  • Organizer: American Heart Association Scientific Session 2014
  • Place of Presentation: Chicago, USA
  • Year and Date: 2014-11-16
• [Presentation] Angiotensin II directly induces mitochondrial dysfunction and atrophy in the skeletal muscle. (2014)
  • Author(s): Kadoguchi T, Kinugawa S, Fukushima A, Furihata T, Suga T, Takada S, Mizushima W, Kudo M, Matsumoto J, Tsuda M, Nishikawa M, Yokota T, Matsushima S, Okita K, Tsutsui H
  • Organizer: American Heart Association Scientific Session 2014.
  • Place of Presentation: Chicago, USA
  • Year and Date: 2014-11-16
• [Presentation] Brain-derived neurotrophic factor maintains exercise capacity and mitochondrial function in the skeletal muscle through AMPK-PGC-1α signaling (2014)
  • Author(s): Takada S, Kinugawa S, Matsushima S, Mizushima W, Fukushima A, Furihata T, Kadoguchi T, Yokota T, Suga T, Okita K, Tsutsui H
  • Organizer: American Heart Association Scientific Session 2014.
  • Place of Presentation: Chicago, USA
  • Year and Date: 2014-11-16
• [Presentation] AST-120 ameliorates lowered exercise capacity and mitochondrial dysfunction of the skeletal muscle in mice with chronic kidney disease via reducing oxidative stress (2014)
  • Author(s): Nishikawa M, Ishimori N, Takada S, Saito A, Kadoguchi T, Furihata T, Fukushima A, Matsushima S, Yokota T, Kinugawa S, Tsutsui H
  • Organizer: American Heart Association Scientific Session 2014.
  • Place of Presentation: Chicago, USA
  • Year and Date: 2014-11-16
• [Presentation] Sesamin improves lowered exercise capacity, mitochondrial dysfunction in the skeletal muscle from high fat diet-induced diabetis mice (2014)
  • Author(s): Takada S, Kinugawa S, Takemoto D, Masaki Y, Kadoguchi T, Yokota T, Matsushima S, Fukushima A, Homma T, Furihata T, Suga T, Katsuyama R, Ono Y, Shibata H, Okita K, Tsutsui H
  • Organizer: 50th European Association for the Study of Diabetes Annual Meetings
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2014-09-18
• [Presentation] Dipeptidyl peptidase-4 inhibitor improved exercise capacity in association with switching to oxidative skeletal muscle fiber type in mice with post-infarct heart failure (2014)
  • Author(s): Masaki Y, Kinugawa S, Takada S, Kadoguchi T, Fukushima A, Homma T, Furihata T, Katsuyama R, Suga T, Takahashi M, Yokota T, Matsushima S, Okita K, Tsutsui H
  • Organizer: 74th American Diabetic Association Scientific Seissions
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2014-06-14
• [Book] 心不全診療の極意 (2016)
  • Author(s): 絹川真太郎、福島新
  • Total Pages: 180
  • Publisher: 南山堂
• [Book] 心不全における骨格筋の重要性・臨床心不全のいちばん大事なところ60 (2014)
  • Author(s): 絹川真太郎
  • Total Pages: 351
  • Publisher: メディカ出版