Nucleus Type-Specific DNA Methylomics Reveals Epigenetic "Memory" of Prior Adaptation in Skeletal Muscle

Using a mouse model of conditional and inducible in vivo fluorescent myonuclear labeling (HSA-GFP), sorting purification of nuclei, low-input reduced representation bisulfite sequencing (RRBS), and a translatable and reversible model of exercise (progressive weighted wheel running, PoWeR), we provide the first nucleus type-specific epigenetic information on skeletal muscle adaptation and detraining. Human skeletal actin promoter reverse tetracycline transactivator tetracycline response element driven histone 2B green fluorescent protein mice (termed HSA-GFP) were generated to label resident myonuclei at the onset of experimentation. A 4-month-old cohort of these mice were subjected to PoWeR for 8 weeks (6 months old when euthanized, 6M PoW, or "trained"), and another cohort was trained then detrained for 12 weeks to reverse training adaptations (9 months old when euthanized, 9M PoW+DT, or "detrained"); age-matched untrained mice served as controls (6M UT and 9M UT).