Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 26, Issue 24, Pages 6019-6031Publisher
WILEY
DOI: 10.1111/jcmm.17618
Keywords
intermittent hypoxia; myokine(s); NRF2; OCT1; sleep apnoea syndrome
Categories
Funding
- Japan Society for the Promotion of Science [21K16344]
- [08102003]
- [15K19425]
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Sleep apnoea syndrome is associated with insulin resistance and type 2 diabetes. Intermittent hypoxia (IH) stimulation increases the expression of muscle-derived insulin resistance factors in muscle cells. OCT1 and NRF2 play important roles in the IH-induced expression of IL-8, ON, and MN genes in muscle cells.
Sleep apnoea 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. The induction of insulin resistance in skeletal muscle is a key phenomenon to develop diabetes. However, the mechanisms linking IH stress and insulin resistance remain elusive. 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. We further analysed the IH-induced expression mechanisms of IL-8, ON, and MN genes in muscle cells. Deletion analyses of the human myokine promoter(s) 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.
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