The effect of intermittent hypoxia on the expression of insulin resistance-related genes in muscle cells

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K16344
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Nara Medical University
• Principal Investigator: Shobatake Ryogo 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 / インスリン抵抗性 / ミオカイン / 睡眠時無呼吸症候群 / 2型糖尿病

Outline of Final Research Achievements

Sleep apnea syndrome is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]) and is a risk factor for insulin resistance/Type 2 diabetes. We exposed human RD and mouse C2C12 muscle cells to normoxia or IH and measured their mRNA levels by real-time RT-PCR. We found that IH significantly increased the mRNA and protein levels of muscle-derived insulin resistance-factors (myokines) such as IL-8, osteonectin (ON), and myonectin (MN) in muscle cells. Deletion analyses revealed that the regions -152 to -151 in IL-8, -105 to -99 in ON, and - 3741 to -3738 in MN promoters were responsible for the activation by IH in RD cells. The promoters contain consensus transcription factor binding sequences for OCT1 in IL-8 and MN promoters, and for NRF2 in ON promoter, respectively. The introduction of siRNA for OCT1 abolished the IH-induced expression(s) of IL-8 and MN and siRNA for NRF2 abolished the IH-induced expression of ON.

Free Research Field

脳神経内科

Academic Significance and Societal Importance of the Research Achievements

睡眠時無呼吸症候群の主病態である間歇的低酸素 （IH）が、インスリン抵抗性に関連するミオカイン遺伝子の発現に与える影響を検討した。IHにより筋細胞においてIL-8、osteonectin (ON)、myonectin (MN) 遺伝子発現が転写レベルで亢進し、IL-8、MNはOCT1、ONはNRF2を転写因子として必要とすることを示した。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。