Studies on the exercise-evoked intramuscular microenvironments and immuno-metabolism regulation

• Project/Area Number: 20H04118
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: Tohoku University
• Principal Investigator: Kanzaki Makoto 東北大学, 医工学研究科, 教授 (10272262)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2022: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2021: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2020: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
• Keywords: 運動 / 骨格筋 / マイオカイン / 運動免疫 / 糖代謝 / ＧＬＵＴ４ / 免疫 / 代謝 / GLUT4 / 筋肉 / 好中球

Outline of Research at the Start

本研究では、最近我々が見出した筋組織内にて運動により一過性に形成される好中球が集積する微小環境（運動筋ニッチ）における異細胞種間の相互的機能連携のシステム制御機構について、マウスの各種運動モデルと生体筋イメージング解析を中核に据えた一連の研究を推進する。特に、この運動筋内の微小領域に動員された好中球と、その局所での良性の免疫代謝調節機構の解明を通して、運動免疫学の新規概念として「運動筋ニッチ」の生理的重要性を確立することを最終目的としている。さらに、運動筋ニッチを経験した運動賦活型免疫細胞が全身を再循環しながら他臓器の免疫代謝機能制御（運動効果の伝搬）にも関与する可能性を検討する

Outline of Final Research Achievements

Muscle contractile activity stimulates intramuscular neutrophil recruitment establishing the microenvironment (exercise-niche) essential for muscular performance. In this research project, we revealed the physiological significance of both CX3CR1- and CXCR2-mediated signals for achieving neutrophil recruitment, upregulation of myokines, enhanced GLUT4 translocation, and adequate endurance capability. Mechanistically, a combination of CX3CR1 and CXCR2 antagonists inhibits exercise-inducible ICAM-1 and fractalkine upregulations around the endothelium and muscle-derived CXCL1 upregulation, both of which contribute to the intramuscular neutrophil accumulation in working muscles. Taken together, the exercise-evoked regional interplay among working myofibers, the adjacent endothelium, and recruited immune cells mediated through these local factors, plays a key role in the organization of the "exercise-niche" supporting the performance of skeletal muscles during exercise.

Academic Significance and Societal Importance of the Research Achievements

運動免疫学の新概念として運動筋ニッチの生理的重要性を確認した。この運動筋ニッチは、運動依存性に惹起される異種多細胞間での相互的機能連携の場であり、その都度異なる運動強度・様式にも最適な生物応答を導き出すための統合システム制御の基点として重要な役割を担っている。本研究では急性期の運動応答性に焦点をあてたが、短期・中長期さらには加齢といった時間軸に沿った運動筋ニッチの変容は筋可塑性の作動原理となる。健全な運動効果発現のみならず、加齢や疾患に起因したそのシステム不全は筋機能、ひいては身体運動機能の弱体化を招く。運動筋ニッチ概念に基づく包括的な筋運動研究は超高齢化社会にある現代社会の吃緊の課題である。

Research Products

• [Journal Article] Effects of CX3CR1 and CXCR2 antagonists on running-dependent intramuscular neutrophil recruitments and myokine upregulation (2023)
  • Author(s): Nyasha MR, Chen W, Wang H, Yaoita F, Aoki M, Nagatomi R, Kanzaki M.
  • Journal Title: Am J Physiol Endocrinol Metab. Volume: 324 Issue: 5 Pages: E375-E389
  • DOI: 10.1152/ajpendo.00196.2022
  • Peer Reviewed / Open Access
• [Journal Article] Undaria pinnatifida (Wakame) Intake Ameliorates High-Fat Diet-Induced Glucose Intolerance via Promoting GLUT4 Expression and Membrane Translocation in Muscle (2023)
  • Author(s): Imai Motoki、Kawakami Fumitaka、Chiba Mutsumi、Kanzaki Makoto、Maruyama Hiroko
  • Journal Title: Journal of Nutrition and Metabolism Volume: 2023 Pages: 1-10
  • DOI: 10.1155/2023/9774157
  • Peer Reviewed
• [Journal Article] Protocol for preparing sensor molecules and analyzing heterotypic endomembrane fusion in insulin-responsive cells using live-cell imaging (2022)
  • Author(s): Hatakeyama H, Kanzaki M.
  • Journal Title: STAR Protoc. Volume: 3 Issue: 4 Pages: 101726-101726
  • DOI: 10.1016/j.xpro.2022.101726
  • Peer Reviewed
• [Journal Article] RSPO3 is a novel contraction-inducible factor identified in an "in vitro exercise model" using primary human myotubes (2022)
  • Author(s): Takahashi T, Li Y, Chen W, Nyasha MR, Ogawa K, Suzuki K, Koide M, Hagiwara Y, Itoi E, Aizawa T, Tsuchiya M, Suzuki N, Aoki M, Kanzaki M.
  • Journal Title: Sci Rep. Volume: 12 Issue: 1 Pages: 14291-14291
  • DOI: 10.1038/s41598-022-18190-z
  • Peer Reviewed
• [Journal Article] Three live-imaging techniques for comprehensively understanding the initial trigger for insulin-responsive intracellular GLUT4 trafficking (2022)
  • Author(s): Hatakeyama H, Kobayashi K, Kanzaki M
  • Journal Title: iScience Volume: 25 Issue: 4 Pages: 104164-104164
  • DOI: 10.1016/j.isci.2022.104164
  • Peer Reviewed
• [Journal Article] Impact of habitual chewing on gut motility via microbiota transition (2022)
  • Author(s): Yaoita Fukie、Watanabe Keita、Kimura Ikuo、Miyazawa Masayuki、Tsuchiya Shinobu、Kanzaki Makoto、Tsuchiya Masahiro、Tan-No Koichi
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 13819-13819
  • DOI: 10.1038/s41598-022-18095-x
  • Peer Reviewed / Open Access
• [Journal Article] リソソーム酵素群の選別輸送に不可欠なニュープレーヤーLYSETの発見 (2022)
  • Author(s): 神﨑 展
  • Volume: 41（1）
  • Pages: 60
  • DOI: 10.18958/7173-00004-0000353-00
• [Journal Article] Tissue accumulation of neutrophil extracellular traps mediates muscle hyperalgesia in a mouse model (2022)
  • Author(s): Suzuki Kazuaki、Tsuchiya Masahiro、Yoshida Shinichirou、Ogawa Kazumi、Chen Weijian、Kanzaki Makoto、Takahashi Tadahisa、Fujita Ryo、Li Yuqing、Yabe Yutaka、Aizawa Toshimi、Hagiwara Yoshihiro
  • Journal Title: Scientific Reports Volume: 12 Issue: 1
  • DOI: 10.1038/s41598-022-07916-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Feeder-supported in vitro exercise model using human satellite cells from patients with sporadic inclusion body myositis (2022)
  • Author(s): Li Yuqing、Chen Weijian、Ogawa Kazumi, ...Suzuki Naoki、Aoki Masashi、Kanzaki Makoto
  • Journal Title: Scientific Reports Volume: 12 Issue: 1
  • DOI: 10.1038/s41598-022-05029-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] プチ断食ダイエットとアンチエイジング効果 (2022)
  • Author(s): 神﨑 展
  • Volume: 40（1）
  • Pages: 59
  • DOI: 10.18958/6941-00004-0000014-00
• [Journal Article] 好中球が骨格筋の糖代謝および運動能力におよぼす作用ー免疫機能との連関－ (2022)
  • Author(s): 神﨑 展
  • Journal Title: 実験医学・増刊号・「健康寿命の鍵を握る骨格筋（藤井宣晴編集） Volume: 40（2） Pages: 200-208
• [Journal Article] Blood glucose-lowering effect of water and ethanolic extracts of Gynura procumbens (Lour.) Merr (2021)
  • Author(s): Aung Cho L.、Kawakami Fumitaka、Imai Motoki、Lwin Thet‐Thet、Kanzaki Makoto、Mar Ohn、Phyu Khin P.、Thwin Mya M.、Maruyama Hiroko
  • Journal Title: Traditional and Kampo Medicine Volume: 8 Issue: 2 Pages: 138-147
  • DOI: 10.1002/tkm2.1277
  • Peer Reviewed
• [Journal Article] Skeletal muscle-specific Keap1 disruption modulates fatty acid utilization and enhances exercise capacity in female mice. (2021)
  • Author(s): Onoki T, Izumi Y, Takahashi M, Murakami S, Matsumaru D, Ohta N, Wati SM, Hatanaka N, Katsuoka F, Okutsu M, Yabe Y, Hagiwara Y, Kanzaki M, Bamba T, Itoi E, Motohashi H*.
  • Journal Title: Redox Biol. Volume: 43 Pages: 101966-101966
  • DOI: 10.1016/j.redox.2021.101966
  • Peer Reviewed / Open Access
• [Journal Article] COVID-19 重篤化の決定的リスクファクター (2021)
  • Author(s): 神﨑 展
  • Journal Title: 2021 実験医学1月号 Volume: 39（1） Pages: 57-58
• [Journal Article] LRRK2 Inhibition Ameliorates Dexamethasone-Induced Glucose Intolerance <i>via</i> Prevents Impairment in GLUT4 Membrane Translocation in Adipocytes (2020)
  • Author(s): Motoki Imai, Fumitaka Kawakami, Makoto Kubo, Makoto Kanzaki, Hiroko Maruyama, Rei Kawashima, Tatsunori Maekawa, Yoshifumi Kurosaki, Fumiaki Kojima, Takafumi Ichikawa.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 43 Issue: 11 Pages: 1660-1668
  • DOI: 10.1248/bpb.b20-00377
  • NAID: 130007934043
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2020-11-01
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Imaging of muscle activity‐induced morphometric changes in fibril network of myofascia by two‐photon microscopy (2020)
  • Author(s): Chaweewannakorn Chayanit、Harada Takashi、Nyasha Mazvita R.、Koide Masashi、Shikama Yosuke、Hagiwara Yoshihiro、Sasaki Keiichi、Kanzaki Makoto、Tsuchiya Masahiro
  • Journal Title: Journal of Anatomy Volume: 238 Issue: 3 Pages: 515-526
  • DOI: 10.1111/joa.13339
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5 (2020)
  • Author(s): Oikawa Yoshitsugu、Izumi Rumiko、Koide Masashi、、、Aoki Masashi、Kure Shigeo、Abe Takaaki
  • Journal Title: PLOS ONE Volume: 15 Issue: 12 Pages: e0231064-e0231064
  • DOI: 10.1371/journal.pone.0231064
  • Peer Reviewed / Open Access
• [Journal Article] Continuous release of O2/ONOO in plasma‐exposed HEPES‐buffered saline promotes TRP channel‐mediated uptake of a large cation (2020)
  • Author(s): Sasaki Shota、Zheng Yuexing、Mokudai Takayuki、Kanetaka Hiroyasu、Tachikawa Masanori、Kanzaki Makoto、Kaneko Toshiro
  • Journal Title: Plasma Processes and Polymers Volume: 17 Issue: 10 Pages: 1900257-1900257
  • DOI: 10.1002/ppap.201900257
  • Peer Reviewed / Open Access
• [Journal Article] Development of optical resolution photoacoustic microscopy with sub-micron lateral resolution for visualization of cells and their structures (2020)
  • Author(s): Shintate Ryo、Morino Taisuke、Kawaguchi Kota、Nagaoka Ryo、Kobayashi Kazuto、Kanzaki Makoto、Saijo Yoshifumi
  • Journal Title: Japanese Journal of Applied Physics Volume: 59 Issue: SK Pages: SKKE11-SKKE11
  • DOI: 10.35848/1347-4065/ab840e
  • Peer Reviewed
• [Journal Article] TRPA1 and TRPV1 channels participate in atmospheric-pressure plasma-induced [Ca2+]i response (2020)
  • Author(s): M. Kawase，W. Chen，K. Kawaguchi，M. R. Nyasha，S. Sasaki，H. Hatakeyama，T. Kaneko，and M. Kanzaki
  • Journal Title: Scientific Reports Volume: 10 Issue: 1
  • DOI: 10.1038/s41598-020-66510-y
  • Peer Reviewed / Open Access
• [Journal Article] Characterization of middle-molecule introduction into cells using mm-scale discharge in saline (2020)
  • Author(s): R. Honda, S. Sasaki, K. Takashima, M. Kanzaki, T. Sato, and T. Kaneko
  • Journal Title: Japanese Journal of Applied Physics Volume: 59 Issue: 4 Pages: 040904-040904
  • DOI: 10.35848/1347-4065/ab7d7e
  • Peer Reviewed
• [Presentation] 肥満・２型糖尿病に対するプラズマ医療の可能性 (2023)
  • Author(s): 神﨑 展
  • Organizer: 東北プラズマフォーラム
  • Invited
• [Presentation] 運動できる“培養”筋細胞系をもちいた基盤研究と新展開 (2023)
  • Author(s): 神﨑 展
  • Organizer: 国際生命科学研究機構（ILSI）シンポジウム
  • Invited
• [Presentation] 運動骨格筋内微小環境（運動筋ニッチ）と運動免疫におけるその重要性 (2022)
  • Author(s): 神﨑 展
  • Organizer: 第７７回日本体力医学会大会・シンポジウム
  • Invited
• [Presentation] Investigations into Physiological Roles of CEFIP, a Novel Contraction-inducible Factor using Knockout Mice; a Gnawing Model Study (2022)
  • Author(s): Mazvita R. Nyasha, Maya Onodera, Weijian Chen, Makoto Kanzaki
  • Organizer: The 17th International Workshop on Biomaterials in Interface Science
• [Presentation] Effect of non-equilibrium atmospheric pressure plasma (APP) on adipocyte browning via modulations of TRPV1 and TRPA1 channels. (2022)
  • Author(s): Weijian Chen, Nyasha M Ruvarashe, Sara Fujii, Yuki Shirakawa, Shota Sasaki, Toshiro Kaneko, Makoto Kanzaki
  • Organizer: ICRP-11, 11th International Conference on Reactive Plasmas.
  • Int'l Joint Research
• [Presentation] 筋・筋膜痛における好中球細胞外トラップの関与 (2021)
  • Author(s): 鈴木 一瑛 , 土谷 昌広 , 神崎 展 , 吉田 新一郎 , 綿貫 宗則 , 矢部 裕 , 藤田 涼 , 高橋 忠久 , 萩原 嘉廣 , 井樋 栄二 , 相澤 俊峰
  • Organizer: 日本整形外科学会
• [Presentation] ヒト収縮型培養筋細胞系で見出した新規マイオカインRspo3の作用機序 (2021)
  • Author(s): 高橋 忠久, 萩原 嘉廣, 神崎 展, 土谷 昌広, 小出 将志, 関口 拓矢, 小川 和美, 李 雨晴, 井樋 栄二, 相澤 俊峰
  • Organizer: 日本整形外科学会
• [Presentation] GLUT4細胞膜移行を制御するインスリン初期作用過程の高精度可視化解析 (2020)
  • Author(s): 神﨑 展 , 畠山 裕康
  • Organizer: 日本糖尿病学会
• [Remarks] elsevierpure: Makoto Kanzaki
  • URL: https://tohoku.pure.elsevier.com/en/persons/makoto-kanzaki
• [Remarks] researchgate:Makoto Kanzaki
  • URL: https://www.researchgate.net/profile/Makoto_Kanzaki/
• [Remarks] 神﨑研HP
  • URL: http://www.ecei.tohoku.ac.jp/kanzaki/index.html
• [Remarks] Elsevier Pure
  • URL: https://tohoku.pure.elsevier.com/en/persons/makoto-kanzaki
• [Remarks] Scopus
  • URL: https://www.scopus.com/authid/detail.uri?authorId=7006880707