リン脂質代謝調節に基づくサルコペニアの新規分子機序の解明

• Project/Area Number: 18K17935
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: Keio University (2020); Juntendo University (2018-2019)
• Principal Investigator: 門口 智泰 慶應義塾大学, 医学部(信濃町), 研究員 (10762049)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Discontinued (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥260,000 (Direct Cost: ¥200,000、Indirect Cost: ¥60,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 筋萎縮 / サルコペニア / リン脂質 / 加齢 / 老化 / ドコサヘキサエン酸 / 心不全

Outline of Annual Research Achievements

令和2年度は、6ヶ月齢の若齢マウスおよび24ヶ月齢に到達した加齢マウスの下肢骨格筋サンプル（腓腹筋）を用い、リピドーム解析によりリン脂質代謝産物を網羅的に観察することで加齢による筋萎縮とリン脂質代謝産物との関連性を調べた。
各群の下肢骨格筋サンプルを対象に、エレクトロスプレーイオン化法を用いた液体クロマトグラフィータンデム質量分析によるエイコサノイド・ドコサノイド解析を実施し、リン脂質代謝産物を同定した。大変興味深いことに、一部のアラキドン酸代謝産物、エイコサペンタエン（EPA）酸代謝産物、ドコサヘキサエン酸（DHA）代謝産物が加齢マウスの萎縮筋において有意に増加し、リノール酸代謝産物においては低下傾向を認めた。中でもEPA代謝産物は加齢マウスの萎縮筋において、より大きな変化を認めていた。このことから、萎縮筋におけるリン脂質代謝、特にEPA代謝異常が加齢に伴う筋萎縮において重要な役割を果たしている可能性が考えられる。
これら代謝産物の変化がどのように起きているのかを明らかにするため、今後は主要なリン脂質代謝酵素であるリゾフォスファチジン酸アシル基転移酵素およびリゾフォスファチジルコリンアシル基転移酵素などとの関連性について検討する必要がある。

Research Products

• [Journal Article] Association of advanced glycation end products with sarcopenia and frailty in chronic kidney disease. (2020)
  • Author(s): Yabuuchi、J., Ueda, S., Yamagishi, S-I, Nohara, N., Nagasawa, H., Wakabayashi, K., Matsui, T., Higashimoto Y., Kadoguchi, T., Otsuka, T., Gohda, T., Suzuki, Y.
  • Journal Title: Sci. Rep. Volume: 10 Issue: 1 Pages: 17647-17659
  • DOI: 10.1038/s41598-020-74673-x
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced monocyte migratory activity in the pathogenesis of structural remodeling in atrial fibrillation (2020)
  • Author(s): Katsutoshi Miyosawa, Hiroshi Iwata, Asuka Minami-Takano, Hidemori Hayashi, Haruna Tabuchi, Gaku Sekita, Tomoyasu Kadoguchi, Kai Ishii, Yui Nozaki, Takehiro Funamizu, Yuichi Chikata, Satoshi Matsushita, Atsushi Amano, Masataka Sumiyoshi, Yuji Nakazato, Hiroyuki Daida, Tohru Minamino
  • Journal Title: PLoS ONE Volume: 15 Issue: 10 Pages: 1-16
  • DOI: 10.1371/journal.pone.0240540
  • Peer Reviewed / Open Access
• [Journal Article] Voluntary exercise and cardiac remodeling in a myocardial infarction model (2020)
  • Author(s): Shahi Hamad Al、Kadoguchi Tomoyasu、Shimada Kazunori、Fukao Kosuke、Matsushita Satoshi、Aikawa Tatsuro、Ouchi Shohei、Shiozawa Tomoyuki、Takahashi Shuhei、Sato-Okabayashi Yayoi、Akita Koji、Isoda Kikuo、Miyazaki Tetsuro、Daida Hiroyuki
  • Journal Title: Open Medicine Volume: 15 Issue: 1 Pages: 545-555
  • DOI: 10.1515/med-2020-0109
  • Peer Reviewed / Open Access
• [Journal Article] Low-dose oral cyclophosphamide therapy reduces atherosclerosis progression by decreasing inflammatory cells in a murine model of atherosclerosis (2020)
  • Author(s): Sato-Okabayashi Yayoi、Isoda Kikuo、Heissig Beate、Kadoguchi Tomoyasu、Akita Koji、Kitamura Kenichi、Shimada Kazunori、Hattori Koichi、Daida Hiroyuki
  • Journal Title: IJC Heart & Vasculature Volume: 28 Pages: 100529-100529
  • DOI: 10.1016/j.ijcha.2020.100529
  • Peer Reviewed / Open Access
• [Journal Article] Association between the tissue accumulation of advanced glycation end products and exercise capacity in cardiac rehabilitation patients (2020)
  • Author(s): Kunimoto Mitsuhiro、Shimada Kazunori、Yokoyama Miho、Matsubara Tomomi、Aikawa Tatsuro、Ouchi Shohei、Shimizu Megumi、Fukao Kosuke、Miyazaki Tetsuro、Kadoguchi Tomoyasu、Fujiwara Kei、Abulimiti Abidan、Honzawa Akio、Yamada Miki、Shimada Akie、Yamamoto Taira、Asai Tohru、Amano Atsushi、Smit Andries J.、Daida Hiroyuki
  • Journal Title: BMC Cardiovascular Disorders Volume: 20 Issue: 1 Pages: 195-195
  • DOI: 10.1186/s12872-020-01484-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Heterogeneity in the vasodilatory function of individual extremities. (2020)
  • Author(s): Kadoguchi T, Horiuchi M, Kinugawa S, Okita K.
  • Journal Title: Vascular Volume: 28 Issue: 1 Pages: 87-95
  • DOI: 10.1177/1708538119868411
  • Peer Reviewed
• [Journal Article] Promotion of oxidative stress is associated with mitochondrial dysfunction and muscle atrophy in aging mice (2019)
  • Author(s): Kadoguchi Tomoyasu、Shimada Kazunori、Miyazaki Tetsuro、Kitamura Kenichi、Kunimoto Mitsuhiro、Aikawa Tatsuro、Sugita Yurina、Ouchi Shohei、Shiozawa Tomoyuki、Yokoyama‐Nishitani Miho、Fukao Kosuke、Miyosawa Katsutoshi、Isoda Kikuo、Daida Hiroyuki
  • Journal Title: Geriatrics & Gerontology International Volume: 20 Issue: 1 Pages: 78-84
  • DOI: 10.1111/ggi.13818
  • Peer Reviewed / Open Access
• [Journal Article] Promotion of oxidative stress is associated with mitochondrial dysfunction and muscle atrophy in aging mice. (2019)
  • Author(s): Kadoguchi T, Shimada K, Miyazaki T, Kitamura K, Kunimoto M, Aikawa T, Sugita Y, Ouchi S, Shiozawa T, Yokoyama-Nishitani M, Fukao K, Miyosawa K, Isoda K, Daida H.
  • Journal Title: Geriatr Gerontol Int. Volume: 20 Pages: 78-84
  • Peer Reviewed / Open Access
• [Journal Article] Associations among circulating levels of follistatin-like 1, clinical parameters, and cardiovascular events in patients undergoing elective percutaneous coronary intervention with drug-eluting stents. (2019)
  • Author(s): Aikawa T, Shimada K, Miyauchi K, Miyazaki T, Sai E, Ouchi S, Kadoguchi T, Kunimoto M, Joki Y, Dohi T, Okazaki S, Isoda K, Ohashi K, Murohara T, Ouchi N, Daida H.
  • Journal Title: PLoS One. Volume: 14
  • Peer Reviewed / Open Access
• [Journal Article] Lack of IκBNS promotes cholate-containing high-fat diet-induced inflammation and atherogenesis in low-density lipoprotein (LDL) receptor-deficient mice. (2019)
  • Author(s): Kitamura K, Isoda K, Akita K, Miyosawa K, Kadoguchi T, Shimada K, Daida H.
  • Journal Title: Int J Cardiol Heart Vasc. Volume: 23 Pages: 100344-100344
  • Peer Reviewed
• [Journal Article] Relationship between the Kihon Checklist and the clinical parameters in patients who participated in cardiac rehabilitation. (2019)
  • Author(s): Kunimoto M, Shimada K, Yokoyama M, Matsubara T, Aikawa T, Ouchi S, Shimizu M, Fukao K, Miyazaki T, Kadoguchi T, Fujiwara K, Honzawa A, Yamada M, Shimada A, Yamamoto T, Amano A, Daida H.
  • Journal Title: Geriatr Gerontol Int. Volume: 19 Pages: 287-292
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of interleukin-1 suppresses angiotensin II-induced aortic inflammation and aneurysm formation. (2018)
  • Author(s): Isoda K, Akita K, Kitamura K, Sato-Okabayashi Y, Kadoguchi T, Isobe S, Ohtomo F, Sano M, Shimada K, Iwakura Y, Daida H
  • Journal Title: Int J Cardiol Volume: 270 Pages: 221-227
  • DOI: 10.1016/j.ijcard.2018.05.072
  • Peer Reviewed / Open Access
• [Journal Article] Correlation of Nutritional Indices on Admission to the Coronary Intensive Care Unit with the Development of Delirium (2018)
  • Author(s): Sugita Yurina、Miyazaki Tetsuro、Shimada Kazunori、Shimizu Megumi、Kunimoto Mitsuhiro、Ouchi Shohei、Aikawa Tatsuro、Kadoguchi Tomoyasu、Kawaguchi Yuko、Shiozawa Tomoyuki、Takasu Kiyoshi、Hiki Masaru、Takahashi Shuhei、Sumiyoshi Katsuhiko、Iwata Hiroshi、Daida Hiroyuki
  • Journal Title: Nutrients Volume: 10 Issue: 11 Pages: 1712-1712
  • DOI: 10.3390/nu10111712
  • Peer Reviewed / Open Access
• [Presentation] Levels of phospholipids and triacylglycerol-containing omega 3 fatty acids in myocardial tissue of patients with myocardial infarction: analyzed by a lipidomics profiling method (2020)
  • Author(s): Shiozawa T, Shimada K, Lee HC, Kadoguchi T, Aikawa T, Hayashi H, Miyazaki T, Matsushita S, Suwa S, Yokomizo T, Amano A, Nakazato Y, Daida H
  • Organizer: European society of cardiology
  • Int'l Joint Research
• [Presentation] Blocking of interleukin-1 suppresses both angiotensin II-induced renal inflammation and hypertension (2020)
  • Author(s): Niida T, Isoda K, Kitamura K, Sato-Okabayashi Y, Kadoguchi T, Ohtomo F, Shimada K
  • Organizer: European society of cardiology
  • Int'l Joint Research
• [Presentation] Relationship between skin autofluorescence levels and clinical outcomes in heart failure patients undergoing cardiac rehabilitation (2019)
  • Author(s): Kunimoto M, Shimada K, Yokoyama M, Honzawa A, Yamada M, Matsubara T, Fukao K, Kadoguchi T, Fujiwara K, Miyazaki T, Yamamoto T, Takahashi T, Fujiwara T, Amano A, Daida H.
  • Organizer: European Society of Congress 2019
  • Int'l Joint Research
• [Presentation] Lack of IkBNS promotes cholate-containing high-fat diet-induced inflammation and atherogenesis in low-density lipoprotein (LDL) receptor-deficient mice. (2019)
  • Author(s): Kitamura K, Isoda K, Akita K, Miyosawa K, Kadoguchi T, Shimada K, Daida H.
  • Organizer: European Society of Congress 2019
  • Int'l Joint Research
• [Presentation] Voluntary exercise associated with myokine production ameliorates cardiac remodeling and inflammation in a myocardial infarction mouse model. (2019)
  • Author(s): Kadoguchi T, Shimada K, Hamad A, Aikawa T, Ouchi S, Kitamura K, Kunimoto M, Fukao K, Yokoyama M, Sugita Y, Shiozawa T, Matsushita S, Miyazaki T, Isoda K, Daida H.
  • Organizer: European Society of Congress 2019
  • Int'l Joint Research
• [Presentation] Prognostic Impact of Peak Oxygen Uptake and Heart Rate Reserve in Patients After Off-pump Coronary Artery Bypass Grafting (2019)
  • Author(s): Abulimiti A, Shimada K, Yokoyama M, Kunimoto M, Matsubara T, Fujiwara K, Aikawa T, Ouchi S, Shimizu M, Fukao F, Kadoguchi T, Miyazaki T, Shimada A, Yamamoto T, Takahashi T, Fujiwara T, Amano A, Daida H.
  • Organizer: European Society of Congress 2019
  • Int'l Joint Research
• [Presentation] Angiotensin II-dependent Activation of NADPH Oxidase 4 Contributes to Muscle Wasting in Mice via Downregulation of NF-E2-related Factor 2. (2018)
  • Author(s): Kadoguchi T, Shimada K, Miyazaki T, Aikawa T, Ouchi S, Kitamura K, Kunimoto M, Sugita Y, Shiozawa T, Isoda K, Daida H
  • Organizer: European Society of Congress 2018
  • Int'l Joint Research
• [Presentation] Malnutrition and Low Omega 6 PUFA Levels on Admission Affect the Development of Delirium in Patients With Acute Cardiovascular Disease Admitted to Coronary Care Unit (2018)
  • Author(s): Sugita Y, Miyazaki T, Shimada K, Shimizu M, Kunimoto M, Aikawa T, Ouchi S, Kadoguchi T, Kawaguchi Y, Shiozawa T, Takasu K, Hiki M, Takahashi S, Yokoyama M, Iwata H, Daida H
  • Organizer: American Heart Association Scientific Sessions 2018
  • Int'l Joint Research
• [Presentation] 心不全における心筋および骨格筋炎症に対する自発運動の効果の検討 (2018)
  • Author(s): 門口智泰, 島田和典, Hamad Al Shahi, 國本充洋, 代田浩之
  • Organizer: 第73回日本体力医学会大会
• [Presentation] 大動脈瘤モデルマウスにおける短期間メトトレキサート投与効果の検討 (2018)
  • Author(s): 大内翔平, 宮崎哲朗, 島田和典, 杉田有里那, 門口智泰, 清水めぐみ, 相川達郎, 塩澤知之, 高橋秀平, 代田浩之
  • Organizer: 日本内科学会
• [Presentation] アンジオテンシンIIによる筋萎縮におけるNADPH oxidaseの働き (2018)
  • Author(s): 門口智泰, 島田和典, 小出 寛, 宮崎哲朗,相川達郎, 大内翔平, 塩澤知之, 高橋秀平, 喜多村健一, 國本充洋, 杉田有里那, 秋田耕嗣, 磯田菊生, 代田浩之
  • Organizer: 第6回骨格筋生物学研究会