212-OR: Differential Cell-Type-Specific Gene Expression and Chromatin Accessibility by Type 2 Diabetes Status and Physical Activity Levels in Human Skeletal Muscle

Introduction: Skeletal muscle plays a role in regulation of glucose metabolism, and physical activity is a preventive factor for type 2 diabetes (T2D). To understand the relationships of T2D status and vigorous physical activity with gene expression and chromatin regulation in skeletal muscle cell types, we analyzed skeletal muscle single nucleus RNA-sequencing and ATAC-sequencing data from 279 Finnish adults from the FUSION Tissue Biopsy Study. Methods: Participants had varying glucose tolerance, ranging from normal glucose tolerance (NGT) to newly-diagnosed T2D, based on an oral glucose tolerance test. We estimated the level of 12-month vigorous physical activity (VPA) based on a questionnaire. Nucleus-level data were clustered using LIGER. We used negative binomial models to test for associations between glucose tolerance or VPA and cell-type composition, gene expression, or chromatin accessibility (genes: 23,841; peaks: 924,519). Results: Participants were 60.2 (SD 7.4) years-of-age, and 41.5% were female, where 102 participants had NGT and 72 had T2D. Of 12 cell types, individuals with lower VPA had a higher proportion of type 2x muscle fibers (Log2 fold change=0.96, p=3.9e-2) with no significant difference by T2D status. Across muscle fiber types, associated genes generally had the same direction of gene expression when having higher VPA or NGT (as compared to T2D). We observed a similar pattern for chromatin accessibility. For example, in type 1 muscle fiber, NGT (as compared to T2D) or higher VPA were each associated with higher expression of cellular respiration genes (VPA: OR=1.77, p=1.4e-9, T2D vs. NGT: OR=0.80, p=8.9e-5) and lower expression of protein K48-linked polyubiquitination genes (VPA: OR=0.64, p=5.2e-3, T2D vs. NGT: OR=2.03, p=6.2e-5). Conclusion: These findings suggest that both normal glucose tolerance and higher vigorous physical activity have similar regulatory effects on gene expression. Disclosure D. Ciotlos: None. S. Hanks: None. A. Varshney: None. M. Erdos: None. N. Manickam: Employee; 10x Genomics. H.M. Stringham: None. E. Hill-Burns: Other Relationship; GE HealthCare. P. Orchard: None. N. Narisu: None. L.L. Bonnycastle: None. M.D. Sweeney: None. M. Laakso: None. J. Tuomilehto: Stock/Shareholder; Orion Pharma, Aktivolabs, Digostics. T.A. Lakka: None. K.L. Mohlke: None. M. Boehnke: None. H.A. Koistinen: Other Relationship; AstraZeneca, Novo Nordisk. F.S. Collins: None. S. Parker: Research Support; Pfizer Inc. L. Scott: None.