Glucocorticoids differentially regulate the skeletal muscle transcriptome in response to acute aerobic exercise at distinct times of day

Abstract

Adaptations to the skeletal muscle following long term aerobic exercise training are mediated at least in part by transcriptional changes that occur in response to each bout of exercise. There is evidence that glucocorticoids induce transcriptional changes in the skeletal muscle in response to a bout of aerobic exercise, but the extent of these changes and whether time of day exercise affects the glucocorticoid transcriptional response is unknown. The purpose of this study was to define changes to the skeletal muscle glucocorticoid transcriptome in response to acute aerobic exercise at different times of day. A secondary purpose was to define the role of Regulated in Development and DNA Damage 1 (REDD1) in mediating these changes as REDD1 is not only a transcriptional target of the glucocorticoid receptor, but it can also modulate glucocorticoid receptor transcriptional activity. A list of glucocorticoid target genes whose expression is altered in the skeletal muscle at various times of day in response to acute exercise was generated by comparing published genomic data sets from rodents subjected to acute aerobic exercise in the light or dark cycles to published genomic data sets from C2C12 myotubes treated with Dexamethasone. The role of glucocorticoid receptor signaling to the genomic changes was assessed in exercised mice treated with RU‐486. The role of REDD1 in mediating the changes to the glucocorticoid transcriptome was assessed in mice lacking REDD1. Glucocorticoids modulated expression of numerous genes in the skeletal muscle in response to acute aerobic exercise in the light and dark cycles, including those that are a target of, or contribute to, ubiquitin conjugation. The extent of changes to the glucocorticoid transcriptome was greater when exercise was conducted in the dark cycle compared to the light cycle. Only some genes encoding proteins involved in ubiquitin conjugation were induced by exercise at both times of day. REDD1 is required for the induction of these genes, whereas those only induced in the light cycle did not require REDD1. The time of day at which aerobic exercise is conducted dictates the extent of changes to the glucocorticoid transcriptome in skeletal muscle. REDD1 is a transducer mediating the time‐of‐day changes to the glucocorticoid transcriptome in skeletal muscle.