間歇的低酸素が筋細胞においてインスリン抵抗性関連遺伝子発現に与える影響

2022 Fiscal Year Annual Research Report

• Project/Area Number: 21K16344
• Research Institution: Nara Medical University
• Principal Investigator: 正畠 良悟 奈良県立医科大学, 医学部, 博士研究員 (40771027)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Keywords: 間歇的低酸素 / 糖尿病 / インスリン抵抗性 / ミオカイン

Outline of Annual Research Achievements

睡眠時無呼吸症候群の病態である間歇的低酸素 (intermittent hypoxia; IH) が、インスリン依存性グルコース取り込みの主要組織である骨格筋に与える影響を検討した。2%ウマ血清で分化させたマウスC2C12筋細胞とヒトRD筋細胞をIH [5分間のO2 1%状態と10分間のO2 21%状態 (Normoxia) の繰り返し] とNormoxiaにそれぞれ24時間曝露後、real-time RT-PCR法でNOX2, GLUT4, MAPK14, PI3KR2, sirtuin 2, TNFα, IL-6, IL-8, IL-15, BDNF, irisin, decorin, osteonectin (ON), myonectin (MN)のmRNAを測定した。IHにより糖尿病関連ミオカインIL-8、ON、MNのmRNA量が有意に増加し、ELISA法では培養上清中の発現蛋白量も有意に増加した。これら3遺伝子のプロモーターアッセイでは、IHによる活性上昇が認められ、IL-8、ON、MN遺伝子のそれぞれ -152～-151、-105～-99、-3741～-3738のプロモーター領域が必要であることがわかった。それらの領域はIL-8、MNに関してはOCT1、ONはNRF2のコンセンサス領域を有しており、それぞれのsiRNA導入によりIL-8、ON、MN遺伝子のIHによる転写活性亢進は消失した。SAS患者では、IL-8、ON、MNの遺伝子発現増加が、筋肉組織において炎症性表現型を誘導し、インスリン抵抗性に寄与していると考えられた(J. Cell. Mol. Med. 2022;24:6019-6031. doi: 10.1111/jcmm.17618; Int. J. Mol. Sci. 2022;23:364. DOI: 10.3390/ijms23010364; Int. J. Mol. Sci. 2022;23:12957. DOI: 10.3390/ijms232112957)。

Research Products

• [Journal Article] Autoimmune Encephalitis Associated with Anti-N-methyl-D-aspartate Receptor and Anti-Hu Antibodies Successfully Treated with Carboplatin and Etoposide for Small-cell Lung Cancer (2023)
  • Author(s): Shobatake Ryogo、Kumazawa Aya、Koyama Noriko、Takahashi Nobuyuki
  • Journal Title: Internal Medicine Volume: 62 Pages: 469～474
  • DOI: 10.2169/internalmedicine.9707-22
  • Peer Reviewed / Open Access
• [Journal Article] Intermittent Hypoxia Increased the Expression of DBH and PNMT in Neuroblastoma Cells via MicroRNA-375-Mediated Mechanism (2022)
  • Author(s): Takasawa Shin、Shobatake Ryogo、Takeda Yoshinori、Uchiyama Tomoko、Yamauchi Akiyo、Makino Mai、Sakuramoto-Tsuchida Sumiyo、Asai Keito、Ota Hiroyo、Itaya-Hironaka Asako
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Pages: 5868～5868
  • DOI: 10.3390/ijms23115868
  • Peer Reviewed / Open Access
• [Journal Article] Downregulation of the Cd38-Cyclic ADP-Ribose Signaling in Cardiomyocytes by Intermittent Hypoxia via Pten Upregulation (2022)
  • Author(s): Takasawa Shin、Makino Mai、Uchiyama Tomoko、Yamauchi Akiyo、Sakuramoto-Tsuchida Sumiyo、Itaya-Hironaka Asako、Takeda Yoshinori、Asai Keito、Shobatake Ryogo、Ota Hiroyo
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Pages: 8782～8782
  • DOI: 10.3390/ijms23158782
  • Peer Reviewed / Open Access
• [Journal Article] Age and composition of the thrombus retrieved by mechanical thrombectomy from patients with acute ischemic stroke are associated with revascularization and clinical outcomes (2022)
  • Author(s): Shimizu Hisao、Hatakeyama Kinta、Saito Kozue、Shobatake Ryogo、Takahashi Nobuyuki、Deguchi Jun、Tokunaga Hidemori、Shimada Keiji、Nakagawa Ichiro、Myochin Kaoru、Sakai Kazuya、Kubo Masayuki、Yamashita Atsushi、Obayashi Chiho、Sugie Kazuma、Matsumoto Masanori
  • Journal Title: Thrombosis Research Volume: 219 Pages: 60～69
  • DOI: 10.1016/j.thromres.2022.09.004
  • Peer Reviewed
• [Journal Article] Upregulation of Reg IV and Hgf mRNAs by Intermittent Hypoxia via Downregulation of microRNA-499 in Cardiomyocytes (2022)
  • Author(s): Takasawa Shin、Itaya-Hironaka Asako、Makino Mai、Yamauchi Akiyo、Sakuramoto-Tsuchida Sumiyo、Uchiyama Tomoko、Shobatake Ryogo、Takeda Yoshinori、Ota Hiroyo
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Pages: 12414～12414
  • DOI: 10.3390/ijms232012414
  • Peer Reviewed / Open Access
• [Journal Article] The Impact of Intermittent Hypoxia on Metabolism and Cognition (2022)
  • Author(s): Shobatake Ryogo、Ota Hiroyo、Takahashi Nobuyuki、Ueno Satoshi、Sugie Kazuma、Takasawa Shin
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Pages: 12957～12957
  • DOI: 10.3390/ijms232112957
  • Peer Reviewed / Open Access
• [Journal Article] Upregulation of IL‐8, osteonectin, and myonectin mRNAs by intermittent hypoxia via OCT1‐ and NRF2‐mediated mechanisms in skeletal muscle cells (2022)
  • Author(s): Takasawa Shin、Shobatake Ryogo、Itaya‐Hironaka Asako、Makino Mai、Uchiyama Tomoko、Sakuramoto‐Tsuchida Sumiyo、Takeda Yoshinori、Ota Hiroyo、Yamauchi Akiyo
  • Journal Title: Journal of Cellular and Molecular Medicine Volume: 26 Pages: 6019～6031
  • DOI: 10.1111/jcmm.17618
  • Peer Reviewed / Open Access
• [Presentation] Intermittent Hypoxia and Appetite Regulation in the Gut-Brain Axis (2023)
  • Author(s): Ryogo Shobatake, Nobuyuki Takahashi, Satoshi Ueno, Kazuma Sugie, Shin Takasawa
  • Organizer: 13th Annual World Congress of NeuroTalk-2023
  • Invited
• [Presentation] 間歇的低酸素は血管内皮細胞のICAM-1, ESM1 mRNAを増加させる (2023)
  • Author(s): 高沢 伸, 牧野 舞, 山内 晶世, 土田 澄代, 廣田 梨奈, 藤井 龍星, 朝井 啓斗, 竹田善紀, 内山 智子,正畠 良悟, 太田 浩世
  • Organizer: 第66回日本糖尿病学会年次学術集会
• [Presentation] Intermittent Hypoxia Increased the Expression of Intercellular Adhesion Molecule-1 and Endothelial Cell-Specific Molecule 1 in Vascular Endothelial Cells via the Downregulation of MicroRNA-181a1 (2023)
  • Author(s): Shin Takasawa, Mai Makino, Akiyo Yamauchi, Sumiyo Sakuramoto-Tsuchida, Rina Hirota, Ryusei Fujii, Keito Asai, Yoshinori Takeda, Tomoko Uchiyama, Ryogo Shobatake, Hiroyo Ota
  • Organizer: 83rd ADA Scientific Sessions
  • Int'l Joint Research
• [Presentation] Gene expression of cardiomyocytes by intermittent hypoxia: the Cd38-cyclic ADP-ribose (cADPR) signaling for functioning and the Reg-Reg receptor system for regeneration (2023)
  • Author(s): Shin Takasawa, Mai Makino, Tomoko Uchiyama, Akiyo Yamauchi, Sumiyo Sakuramoto-Tschida, Asako Itaya-Hironaka, Yoshinori Takeda, Keito Asai, Ryogo Shobatake, Hiroyo Ota
  • Organizer: 4th Edition of World Congress on ENDOCRINOLOGY, DIABETES AND METABOLISM
  • Int'l Joint Research
• [Presentation] Intermittent hypoxia increased the expression of DBH and PNMT in neuronal cells via microRNA-mediated mechanism. (2022)
  • Author(s): Takasawa, S., Shobatake, R., Takeda, Y., Uchiyama, T., Yamauchi, A., Makino, M., Asai, K. and Ota, H.
  • Organizer: 82nd American Diabetes Association Scientific Sessions, June 3-7, 2022, New Orleans, LA, Hybrid Diabetes 71 (Suppl. 1), 1317-P (2022).
  • Int'l Joint Research
• [Presentation] Attenuation of the CD38-cADPR signal system in cardiomyocytes by intermittent hypoxia via upregulation of Pten (2022)
  • Author(s): Shin Takasawa, Mai Makino, Tomoko Uchiyama, Akiyo Yamauchi, Sumiyo Sakuramoto-Tsuchida, Asako Itaya-Hironaka, Yoshinori Takeda, Keito Asai, Ryogo Shobatake, Hiroyo Ota
  • Organizer: International Diabetes Federation (IDF)