The role of iron on sarcopenia, and the therapeutic significance of iron regulation for anti-sarcopenia

• Project/Area Number: 15K01716
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied health science
• Research Institution: The University of Tokushima
• Principal Investigator: IKEDA Yasumasa 徳島大学, 大学院医歯薬学研究部(医学系), 准教授 (60432754)
• Co-Investigator(Kenkyū-buntansha): 八木 秀介 徳島大学, 大学院医歯薬学研究部, 特任准教授 (00507650)
• Co-Investigator(Renkei-kenkyūsha): HORINOUCHI Yuya 徳島大学, 大学院医歯薬学研究部(医学系), 助教 (30716593)
• Research Collaborator: HAMANO Hirofumi 徳島大学, 大学院医歯薬学研究部(医学系), 大学院生 ; IMAO Mizuki 徳島大学, 大学院医歯薬学研究部(薬学系), 学部生 ; SATO Akiho 徳島大学, 大学院医歯薬学研究部(薬学系), 学部生 ; WATANABE Hiroaki 徳島大学, 大学院医歯薬学研究部(薬学系), 学部生
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 鉄 / サルコペニア / 酸化ストレス / 骨格筋 / 骨格筋萎縮 / ユビキチンリガーゼ

Outline of Final Research Achievements

Skeletal muscle atrophy is a critical health problem. However, the effect of iron on skeletal muscle atrophy has remained unclear. Mice with excess iron-injected group showed the reduced skeletal muscle mass. The skeletal muscle with iron treatment showed elevated mRNA expression of the muscle atrophy-related E3 ubiquitin ligases, atrogin-1 and muscle ring finger-1(MuRF1). Moreover, iron-treated mice showed reduced phosphorylation of Akt and forkhead box O3 (FOXO3a) in skeletal muscles. In in vitro experiments using C2C12 myotube cells, FOXO3a siRNA inhibited iron-induced upregulation of atrogin-1 and MuRF1 and reversed the reduction in myotube diameters. Iron-load caused oxidative stress, and an oxidative stress inhibitor abrogated iron-induced muscle atrophy by recovering the reduced phosphorylation of Akt-FOXO3a pathway. Iron-induced skeletal muscle atrophy is suggested to involve the inactivation of Akt-FOXO3a-E3 ubiquitin ligase signaling by oxidative stress.

Research Products

• [Journal Article] The uremic toxin indoxyl sulfate interferes with iron metabolism by regulating hepcidin in chronic kidney disease (2018)
  • Author(s): Hirofumi Hamano, Yasumasa Ikeda, Hiroaki Watanabe, Yuya Horinouchi, Yuki Izawa-Ishizawa, Masaki Imanishi, Yoshito Zamami, Kenshi Takechi, Licht Miyamoto, Keisuke Ishizawa, Koichiro Tsuchiya and Toshiaki Tamaki
  • Journal Title: Nephrology Dialysis Transplantion Volume: - Pages: 586-597
  • DOI: 10.1093/ndt/gfx252
  • Peer Reviewed / Open Access
• [Journal Article] Hydrocortisone administration was associated with improved survival in Japanese patients with cardiac arrest. (2017)
  • Author(s): 48)Niimura T, Zamami Y, Koyama T, Izawa-Ishizawa Y, Miyake M, Koga T, Harada K, Ohshima A, Imai T, Kondo Y, Imanishi M, Takechi K, Fukushima K, Horinouchi Y, Ikeda Y, Fujino H, Tsuchiya K, Tamaki T, Hinotsu S, Kano MR, Ishizawa K.
  • Journal Title: Sci Rep. Volume: 7 Pages: 17919-17919
  • DOI: 10.1038/s41598-017-17686-3
  • NAID: 120006535027
  • Peer Reviewed / Open Access
• [Journal Article] Nitrite Activates 5′AMP-Activated Protein Kinase-Endothelial Nitric Oxide Synthase Pathway in Human Glomerular Endothelial Cells (2017)
  • Author(s): Miyamoto Licht、Yamane Megumi、Tomida Yosuke、Kono Mai、Yamaoka Tomomi、Kawasaki Aya、Hatano Aya、Tsuda Katsunori、Xu Wenting、Ikeda Yasumasa、Tamaki Toshiaki、Tsuchiya Koichiro
  • Journal Title: Biol. Pharm. Bull. Volume: 40 Issue: 11 Pages: 1866-1872
  • DOI: 10.1248/bpb.b17-00316
  • NAID: 130006191905
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access
• [Journal Article] Dietary iron restriction alleviates renal tubulointerstitial injury induced by protein overload in mice (2017)
  • Author(s): Yasumasa Ikeda, Yuya Horinouchi, Hirofumi Hamano, Tasuku Hirayama, Seiji Kishi, Yuki Izawa-Ishizawa, Masaki Imanishi, Yoshito Zamami, Kenshi Takechi, Licht Miyamoto, Keisuke Ishizawa, Ken-ichi Aihara, Hideko Nagasawa, Koichiro Tsuchiya, and Toshiaki Tamaki
  • Journal Title: Sci Rep Volume: 7 Pages: 10621-10621
  • DOI: 10.1038/s41598-017-11089-0
  • NAID: 120006534998
  • Peer Reviewed / Open Access
• [Journal Article] The Role of Heparin Cofactor Ⅱ in the Regulation of Insulin Sensitivity and Maintenance of Glucose Homeostasis in Humans and Mice (2017)
  • Author(s): Kurahashi K, Inoue S, Yoshida S, Ikeda Y, Morimoto K, Uemoto R, Ishikawa K, Kondo T, Yuasa T, Endo I, Miyake M, Oyadomari S, Matsumoto T, Abe M, Sakaue H, Aihara KI.
  • Journal Title: J Atheroscler Thromb Volume: 24 Issue: 12 Pages: 1215-1230
  • DOI: 10.5551/jat.37739
  • NAID: 130006235273
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed / Open Access
• [Journal Article] Iron suppresses erythropoietin expression via oxidative stress-dependent hypoxia-inducible factor-2 alpha inactivation. (2017)
  • Author(s): Oshima K, Ikeda Y, Horinouchi Y, Watanabe H, Hamano H, Kihira Y, Kishi S, Izawa-Ishizawa Y, Miyamoto L, Hirayama T, Nagasawa H, Ishizawa K, Tsuchiya K, Tamaki T
  • Journal Title: Laboratory Investigation volume Volume: 印刷中 Pages: 555-566
  • DOI: 10.1038/labinvest.2017.11
  • Peer Reviewed
• [Journal Article] Topical Application of Nitrosonifedipine, a Novel Radical Scavenger, Ameliorates Ischemic Skin Flap Necrosis in a Mouse Model. (2017)
  • Author(s): Fukunaga Y, Izawa-Ishizawa Y, Horinouchi Y, Sairyo E, Ikeda Y, Ishizawa K,Tsuchiya K, Abe Y, Hashimoto I, Tamaki T
  • Journal Title: Wound Repair Regen. Volume: 印刷中 Pages: 217-223
  • DOI: 10.1111/wrr.12510
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Iron-induced skeletal muscle atrophy involves an Akt-forkhead box O3-E3 ubiquitin ligase-dependent pathway. (2016)
  • Author(s): Yasumasa Ikeda, Mizuki Imao, Akiho Satoh, Hiroaki Watanabe, Hirofumi Hamano, Yuya Horinouchi, Yuki Izawa-Ishizawa, Yoshitaka Kihira, Licht Miyamoto, Keisuke Ishizawa, Koichiro Tsuchiya, Toshiaki Tamaki
  • Journal Title: J Trace Elem Med Biol. Volume: 35 Pages: 66-76
  • DOI: 10.1016/j.jtemb.2016.01.011
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Roles of the Androgen – Androgen Receptor System in Vascular Angiogenesis (2016)
  • Author(s): Sumiko Yoshida, Yasumasa Ikeda and Ken-ichi Aihara
  • Journal Title: J Atheroscler Thromb Volume: 23(3) Issue: 3 Pages: 257-265
  • DOI: 10.5551/jat.31047
  • NAID: 130005131882
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed / Open Access
• [Journal Article] Angiotensin II alters the expression of duodenal iron transporters, hepatic hepcidin, and body iron distribution in mice (2015)
  • Author(s): Soichiro Tajima, Yasumasa Ikeda, Hideaki Enomoto, Imao Mizuki, Yuya Horinouchi, Yuki Izawa-Ishizawa, Yoshitaka Kihira, Rihito Miyamoto, Keisuke Ishizawa, Koichiro Tsuchiya and Toshiaki Tamaki
  • Journal Title: Eur J Nutr. Volume: 印刷中 Pages: 709-719
  • DOI: 10.1007/s00394-014-0749-1
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hypoxia Decreases Glucagon-Like Peptide-1 Secretion from the GLUTag Cell Line (2015)
  • Author(s): Yoshitaka Kihira, Ariunzaya Burentogtokh, Mari Itoh, Yuki Izawa-Ishizawa, Keisuke Ishizawa, Yasumasa Ikeda, Koichiro Tsuchiya, and Toshiaki Tamaki
  • Journal Title: Biol. Pharm. Bull. Volume: 38 Issue: 4 Pages: 514-521
  • DOI: 10.1248/bpb.b14-00612
  • NAID: 130005062264
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Bilirubin exerts pro-angiogenic effects through an Akt-eNOS-dependent pathway (2015)
  • Author(s): Yasumasa Ikeda, Hamano Hirofumi, Satoh Akiho, Horinouchi Yuya, Yuki Izawa-Ishizawa, Yoshitaka Kihira, Keisuke Ishizawa, Ken-ichi Aihara, Koichiro Tsuchiya and Toshiaki Tamaki
  • Journal Title: Hypertens Res. Volume: 38(11) Pages: 733-740
  • DOI: 10.1038/hr.2015.74
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 鉄過剰がもたらす臓器障害リスク (2017)
  • Author(s): 池田康将、玉置俊晃
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎新聞文化ホールアストピア（長崎県・長崎市）
  • Year and Date: 2017-03-15
• [Presentation] 慢性腎不全における尿毒素蓄積が生体内鉄代謝に与える影響の検討 (2017)
  • Author(s): 濱野 裕章、池田 康将、渡邉 大晃、堀ノ内 裕也、佐藤 明穂、大島 啓亮、 石澤 有紀、石澤 啓介、土屋 浩一郎、玉置 俊晃
  • Organizer: 第46回日本心脈管作動物質学会
  • Place of Presentation: 琉球大学医学部（沖縄県・那覇市）
  • Year and Date: 2017-02-10
• [Presentation] Indoxyl Sulfate Disturbs Normal Iron Metabolism via Hepcidin Upregulation in Chronic Kidney Disease, (2017)
  • Author(s): Hirofumi Hamano, Yasumasa Ikeda, Hiroaki Watanabe, Yuya Horinouchi, Yuki Izawa-Ishizawa, Masaki Imanishi, Yoshito Zamami, Kenshi Takechi, Licht Miyamoto, Keisuke Ishizawa, Koichiro Tsuchiya, Toshiaki Tamaki
  • Organizer: ASN Kidney Week 2017
  • Int'l Joint Research
• [Presentation] 鉄摂取制限による尿細管間質障害の抑制効果の検討 (2017)
  • Author(s): 池田 康将, 堀ノ内 裕也, 濱野 裕章, 平山 祐, 岸 誠司, 石澤 有紀, 今西 正樹, 座間味 義人, 武智 研志, 宮本 理人, 石澤 啓介, 粟飯原 賢一, 永澤 秀子, 土屋 浩一郎, 玉置 俊晃
  • Organizer: 第41回日本鉄バイオサイエンス学会学術集会
• [Presentation] IRON RESTRICTION PREVENTS RENAL TUBULOINTERSTITIAL INJURY INDUCED BY ALBUMIN OVERLOAD IN MICE (2017)
  • Author(s): Yasumasa Ikeda, Yuya Horinouchi, Yuki Izawa-Ishizawa, Toshiaki Tamaki
  • Organizer: 54th ERA-EDTA Congress
  • Int'l Joint Research
• [Presentation] DIRECT FACTOR XA INHIBITOR PREVENTS RENAL INTERSTITIAL FIBROSIS IN MICE WITH UNILATERAL URETERAL OBSTRUCTIO (2017)
  • Author(s): Yasumasa Ikeda, Yuya Horinouchi, Yuki Izawa-Ishizawa, Toshiaki Tamaki
  • Organizer: 54th ERA-EDTA Congress
  • Int'l Joint Research
• [Presentation] 鉄摂取制限はタンパク過剰負荷による尿細管間質障害を軽減する (2017)
  • Author(s): 池田 康将, 堀ノ内 裕也, 石澤 有紀, 玉置 俊晃
  • Organizer: 第60回日本腎臓学会学術総会
• [Presentation] Indoxyl Sulfate Involves Abnormality of Iron Metabolism Through Hepcidin Regulation (2017)
  • Author(s): Hirofumi Hamano, Yasumasa Ikeda, Hiroaki Watanabe, Yuya Horinouchi, Yuki Izawa-Ishizawa, Keisuke Ishizawa, Koichiro Tsuchiya, Toshiaki Tamaki
  • Organizer: Experimental Biology 2017
  • Int'l Joint Research
• [Presentation] Excess iron action on risk of tissue injury (2017)
  • Author(s): Yasumasa Ikeda and Toshiaki Tamaki
  • Organizer: 第90回日本薬理学会年会 年会企画ナノシンポジウム 「機能性食品における薬理学」
  • Invited
• [Presentation] 鉄欠乏が骨格筋に与える作用の検討 (2016)
  • Author(s): 佐藤明穂、池田康将、濱野裕章、堀ノ内裕也、今尾瑞季、渡邉大晃、石澤有紀、宮本理人、石澤啓介、玉置俊晃、土屋浩一郎
  • Organizer: 第55回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会
  • Place of Presentation: 岡山コンベンションセンター（岡山県・岡山市）
  • Year and Date: 2016-11-05
• [Presentation] The new insight of iron on tissue damage in metabolic disorders. (2016)
  • Author(s): Yasumasa Ikeda, Yuya Horinouchi, Yuki Izawa-Ishizawa, Toshiaki Tamaki
  • Organizer: The 9th International Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric Oxide/16th Annual Scientific Meeting of the Nitric Oxide Society of Japan.
  • Place of Presentation: 仙台国際センター（宮城県・仙台市）
  • Year and Date: 2016-05-20
  • Int'l Joint Research
• [Presentation] The Involvement of Iron Supplementation on Erythropoietin Expression (2016)
  • Author(s): Yasumasa Ikeda, Oshima Keisuke, Horinouchi Yuya, Yuki Izawa-Ishizawa, Yoshitaka Kihira, Keisuke Ishizawa, Koichiro Tsuchiya and Toshiaki Tamaki
  • Organizer: Experimental Biology 2016
  • Place of Presentation: SanDiego（USA)
  • Year and Date: 2016-04-02
  • Int'l Joint Research
• [Presentation] Iron Supplementation Suppressed Erythropoietin Expression through HIF-Dependent Pathway (2016)
  • Author(s): Yasumasa Ikeda, Keisuke Oshima, Yuya Horinouchi, Yuki Izawa-Ishizawa, Yoshitaka Kihira, Keisuke Ishizawa, Koichiro Tsuchiya, Toshiaki Tamaki
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-03-18
• [Presentation] 慢性腎不全における鉄代謝変化と腎性貧血との関連 (2016)
  • Author(s): 池田 康将
  • Organizer: 第9回慢性腎臓病(CKD)病態研究会
  • Place of Presentation: 東京丸ビルカンファレンスセンター（東京都・千代田区）
• [Presentation] 骨格筋分化における鉄の役割 (2016)
  • Author(s): 池田 康将, 佐藤 明穂, 堀ノ内 裕也, 石澤 有紀, 宮本 理人, 石澤 啓介, 土屋 浩一郎, 玉置 俊晃
  • Organizer: 第129回日本薬理学会近畿部会
  • Place of Presentation: 広島県医師会館（広島県・広島市）
• [Presentation] 臓器障害における生体内鉄代謝の意義と鉄除去による病態改善効果 (2015)
  • Author(s): 池田 康将, 玉置 俊晃
  • Organizer: 心血管代謝週間(CVMW)(第19回日本心血管内分泌代謝学会学術総会) シンポジウム
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-12-10
  • Invited
• [Presentation] Bilirubin Enhances Ischimia-induced Angiogenesis Through Akt-eNOS-Dependent Signaling Pathway (2015)
  • Author(s): Yasumasa Ikeda, Hamano Hirofumi, Horinouchi Yuya, Yuki Izawa-Ishizawa, Yoshitaka Kihira, Keisuke Ishizawa, Koichiro Tsuchiya and Toshiaki Tamaki
  • Organizer: American Heart Association Scientific Sessions 2015
  • Place of Presentation: Orlando, USA
  • Year and Date: 2015-11-06
  • Int'l Joint Research
• [Presentation] 鉄欠乏は骨格筋量減少の原因となる (2015)
  • Author(s): 池田 康将, 佐藤 明穂, 堀ノ内 裕也, 石澤 有紀, 木平 孝高, 石澤 啓介, 土屋 浩一郎, 玉置 俊晃
  • Organizer: 第39回日本鉄バイオサイエンス学会学術集会
  • Place of Presentation: 岡山コンベンションセンター（岡山県岡山市）
  • Year and Date: 2015-08-29
• [Presentation] 心血管疾患における男性ホルモンの意義 (2015)
  • Author(s): 池田 康将, 粟飯原 賢一, 吉田 守美子, 赤池 雅史, 玉置 俊晃, 松本 俊夫
  • Organizer: , 第15回日本抗加齢医学会総会シンポジウム「知って得するテストステロンアップデート」
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2015-05-29
  • Invited
• [Remarks] 徳島大学医学部薬理学分野
  • URL: http://www.tuyakuri.umin.jp/
• [Remarks] 徳島大学薬理学ホームページ
  • URL: http://www.tuyakuri.umin.jp/