Inverse directions of association of higher physical activity and higher insulin resistance with human skeletal muscle fiber-type gene expression

Summary: To investigate the interplay between physical activity and cardiometabolic traits in human skeletal muscle, we characterized gene expression and chromatin accessibility across skeletal muscle cell types in 263 Finnish individuals from the FUSION Tissue Biopsy Study. We analyzed single-nucleus RNA-seq data (168,309 nuclei), single-nucleus ATAC-seq data (242,069 nuclei), and bulk RNA-seq data. Lower insulin resistance (HOMA-IR) and higher total physical activity were both associated with higher proportions of Type 1 nuclei and lower proportions of Type 2x nuclei. Traits typically associated with better health—lower trait values of cardiometabolic traits such as HOMA-IR and higher physical activity levels—were associated with higher expression of energy metabolism genes and lower expression of signaling pathway genes across muscle fiber types, total pseudobulk, and to some extent in bulk tissue. HOMA-IR and physical activity appeared to have inverse and partially independent directions of association when adjusting for both traits in the same model.