124 Skeletal muscle RNA and insulin sensitivity during insufficient sleep. (3rd May 2021) - Morton, Sarah
Abstract: Introduction: Insufficient sleep is associated with a down-regulation of genes involved in glycolysis, in conjunction with an upregulation of genes involved in lipid metabolism in skeletal muscle. However, whether changes in RNA are associated with impairments in insulin sensitivity is unclear. We therefore tested the hypothesis that insufficient sleep will induce alterations in skeletal muscle RNA that correlate with changes in insulin sensitivity. Methods: As part of an ongoing study, sixteen sedentary, healthy, lean adults (24.9±3.4y; 22.6±1.7kg/m2; 6F; mean±SD) participated in a controlled 6-day in-laboratory protocol with 9h in bed (habitual sleep) followed by 4 nights of 5h in bed (insufficient sleep), achieved by delaying bedtime by 4 hours. For one week prior to the study, participants maintained a 9h sleep schedule based on their habitual bed and wake times. Participants consumed energy-balanced diets 3 days prior to and throughout the laboratory protocol. Whole body insulin sensitivity was assessed using glucose infusion rate from a hyperinsulinemic euglycemic clamp before and after 4 nights of insufficient sleep. Skeletal muscle biopsies of the vastus lateralis were taken immediately before each clamp. In a subset of subjects (n=12), RNA sequencing was performed (Novogene Co., Ltd). Generalized linear model likelihood ratio tests were completed using the DESeq2/EdgeR R packages with a false discovery rate (FDR) cut-off of 5%. P-values were adjusted for multiple comparisons using the Benjamini-Hochberg method and a corrected p-value of 0.05 and log2 fold-change of 0 were set as the threshold for statistical significance. Results: Insulin sensitivity was impaired by 6% following insufficient sleep (10.1±1.4 vs 9.1±1.1mg/kg/min, p<0.05, mean±SEM). Preliminary results from skeletal muscle RNAseq analyses suggest approximately 25 genes were down-regulated and 60 genes were up-regulated. Down-regulated genes were involved in insulin-like growth factor binding and signal transduction (p=8.4e-11), while up-regulated genes were involved in glycolysis and ATP binding (p=1.1e-9). While there were trends for associations between changes in gene expression and insulin sensitivity, these relationships did not reach statistical significance. Conclusion: Preliminary findings suggest insufficient sleep alters skeletal muscle RNA. Changes in these aforementioned pathways may contribute to metabolic dysregulation during insufficient sleep. Support (if any): NIH K01DK110138, R03 DK118309, UL1 TR002535, and GCRC RR-00036