Chronic exercise training activates histone turnover in mouse skeletal muscle fibers

Epigenetic regulation of skeletal muscle adaptation to exercise is a recent topic for which there is limited information. This study investigated whether exercise training activates histone turnover in the skeletal muscle fibers of mice. Experiments using a tetracycline-inducible H2B-GFP expression model demonstrated that 4 weeks of running training, but not 2 weeks of training, significantly promoted the incorporation of H2B-GFP into nucleosomes and the dissociation of histone H3.3 at both transcriptionally upregulated and nonresponsive loci. Muscle-specific PGC-1α-b-overexpressing mice crossed with H2B-GFP mice showed a slight increase in H2B-GFP incorporation at transcriptionally active loci, but not in the dissociation of H3.3 from nucleosomes. Gene expression responses to a single bout of running were significantly enhanced in 4-week trained mice when compared with those in 2-week trained mice. The most drastic increase in the gene response was found in the expression of Hspa1a and Hspa1b, in which the magnitude of upregulation in response to running was significantly enhanced from 8-fold in 2 week trained mice to 97- and 121-fold in 4 week trained mice, respectively. It was also found that the HSP70 level increased during the training period. In a myonuclear immunohistochemical analysis of chromatin remodelers, we further found that the level of SPT16, an H2A-H2B-specific chaperone, was upregulated after running training. These results revealed that 4 weeks of running training activated histone turnover in skeletal muscle fibers. They also suggested that histone turnover led to loosening of the nucleosomes and enhanced gene responses to exercise.