Effects of chronic intermittent hypoxia and reoxygenation on insulin resistance and skeletal muscle miR-27a-3p/PPARγ/IRS1/PI3K/AKT expressions in rats

Abstract

To investigate the effects of chronic intermittent hypoxia (CIH) and reoxygenation on insulin resistance (IR) and expressions of miR-27a-3p/PPARγ/IRS1/PI3K/AKT in rat skeletal muscle. GEO database was used for screening the differentially expressed miRNAs in CIH, and their target genes were subjected to GO and KEGG enrichment analysis followed by construction of the miRNA-mRNA-pathway regulatory network using Cytoscape. In the animal experiment, 48 male SD rats were randomly divided into normoxia group and CIH group (8 weeks of CIH followed by 4 weeks of normoxic recovery). Blood and skeletal muscle samples were collected at baseline, 8 weeks, and 12 weeks to evaluate the changes in fasting blood glucose (FBG) and fasting insulin (FINS) levels and muscular pathology. RT-qPCR and Western blotting were used to detect the changes in the expressions of miR-27a-3p, PPARγ, GLUT4, IRS1, p-IRS1, PI3K, p-AKT and AKT in the muscular tissues. No muscular miRNA datasets for CIH were available in GEO database, from which only a kidney-related dataset (GSE202480) was obtained, based on which a total of 165 differentially expressed miRNAs were identified. GO/KEGG analysis suggested that these miRNAs were involved in muscular regulation and insulin signaling. The miRNA-mRNA-pathway network highlighted miR-27a-3p as a crucial regulator in the PPAR and PI3K/AKT pathway. In the animal experiment, the rats subjected to CIH for 8 weeks showed significantly increased FBG, FINS, HOMA-IR, and PPARγ levels, loose muscle fiber arrangement, decreased cross-sectional area of the muscle fibers, and lowered expressions of miR-27a-3p, p-IRS1/IRS1, PI3K, and p-AKT/AKT in the skeletal muscles. CIH increases IR, causes skeletal muscle pathology, downregulates miR-27a-3p expression, upregulates PPARγ expression, and inhibits IRS1/PI3K/AKT insulin signaling in the skeletal muscles of rats, and these changes can be reversed by reoxygenation. MiR-27a-3p may participate in CIH-induced IR by modulating the PPAR γ/IRS1/PI3K/AKT signaling pathway.