Integrated Analysis of Skeletal Muscle Transcriptional Networks Characterizes Dysregulation in Pathways and Trait-Associated Regulatory Regions in Type 2 Diabetes
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Skeletal muscle, a primary site of insulin-mediated glucose uptake, plays a central role in the pathogenesis of type 2 diabetes. It is therefore critical to understand the disease-associated alterations in skeletal muscle and identify the underlying drivers of this dysregulation. Here, we characterize type 2 diabetes associated transcriptional dysregulation using 301 skeletal muscle biopsies from living donors with and without diabetes. Using weighted gene co-expression network analysis, we identify 56 distinct gene modules, which we further characterize using single-nucleus RNA-seq-derived cell type signatures and pathway enrichment analysis. We identify numerous cell type-associated dysregulated pathways in skeletal muscle tissue from individuals with diabetes, including muscle fiber-associated mitochondrial function and mRNA splicing and processing; endothelial vascularization and phospholipase D signaling; and macrophage- and T-cell-associated inflammation. Through analysis of module hub genes and transcription factor regulatory network analysis, we further identify candidate driver genes of this dysregulation including ATP5L , ATF2 , SIRT1, and THRAP3 in muscle fibers; JAM2 and CLEC14A in endothelial cells; and F13A1 and IRF8 in immune cells. Finally, we integrate our co-expression networks with single-nucleus ATAC-seq data to identify proximal and distal genomic regulatory elements and identify context-specific enrichment for type 2 diabetes and related trait GWAS signals in muscle fiber and endothelial modules. Together, our results reveal dysregulation in pathways in muscle tissue from individuals with diabetes, identify candidate drivers, and connect the genomic drivers of this dysregulation across type 2 diabetes and related metabolic traits.
Authors: Avery Maddox, Nandini Manickam, Peter Orchard, Michael R. Erdos, Narisu Narisu, Heather M. Stringham, Timo A. Lakka, Jouko Saramies, Markku Laakso, Jaakko Tuomilehto, Karen L. Mohlke, Michael Boehnke, Laura J. Scott, Heikki A. Koistinen, Francis S. Collins, Arushi Varshney, Arvind Rao, Stephen CJ Parker
Institutions: University of Michigan, National Human Genome Research Institute, University of Eastern Finland, Kuopio University Hospital, Etelä-Karjalan sosiaali ja terveyspiiri, University of Helsinki, Finnish Institute for Health and Welfare, University of North Carolina at Chapel Hill, Helsinki University Hospital, Minerva Foundation
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7203863906