Integrated single-cell multiome analysis resolves muscle fiber-type gene regulatory circuitry modulated by endurance exercise

Endurance exercise is an important health modifier. We studied cell-type specific adaptations of human skeletal muscle to acute endurance exercise using single-nucleus multiome sequencing in human vastus lateralis samples collected before and 3.5 hours after 40 min exercise at 70% VO2 max in four subjects, as well as in matched time of day samples from two supine resting circadian controls. High quality same cell RNAseq and ATACseq data were obtained from 37,154 nuclei comprising 14 cell types. Among muscle fiber types, both shared and fiber-type specific regulatory programs were identified. Comprehensive single cell regulatory circuit analysis identified distinct fiber type programs involving 272 TFs regulating 1579 genes at specific regulated chromatin sites, with fast fibers showing more robust circuit responses. These data and comprehensive circuit reconstruction provide a high resolution map of the molecular adaptations to exercise at single cell resolution.