The skeletal muscle of aged male mice exhibits a sustained growth regulatory transcriptional profile following prolonged glucocorticoid exposure compared to young males

Excess glucocorticoids induce a skeletal muscle myopathy by changing gene expression. Advanced age augments glucocorticoid-mediated muscle phenotypes, although transcriptional responses underlying those augmented phenotypes are unclear. The purpose of this study was to determine glucocorticoid-induced transcriptional landscapes in young and aged muscle following acute exposure to the hormone and following longer glucocorticoid treatment. Young (4-month-old) or aged (24-month-old) male mice were administered an acute injection of dexamethasone (DEX) or vehicle or treated with DEX or vehicle for 7 days. Muscles were harvested 6.5 h after the only/last injection(s). The tibialis anterior (TA) was analyzed because mass was lower following DEX treatment only in aged males. RNA from the TA was subjected to RNA sequencing. In silico analyses determined pathways associated with glucocorticoid-sensitive genes and predicted transcription factors regulating transcriptional changes. Acute DEX altered similar numbers of genes in young (950) vs. aged males (913) although aged males had greater magnitudes of fold change. The transcriptional response in aged males following 7 days of DEX treatment was greater than acute exposure (1,196 vs 913) whereas the transcriptional response in young males was less pronounced after 7 days (599 vs 950). The glucocorticoid-sensitive genes in aged males were related to growth regulation regardless of treatment duration whereas that predominant enrichment was not evident in young males. Despite transcriptional differences, the transcription factors predicted to regulate the glucocorticoid-sensitive genes were similar in young and aged males. These data expand our understanding of transcriptional changes elicited by glucocorticoids in response to advanced age Overall design: Young (4months) and aged (24months) mice were each randomized into 2 groups of equal body weight. One group from each age was given daily subcutaneous injections of saline while the other group from each age was given daily subcutaneous injections of dexamethasone (1mg/kg/day). Injections were administered for 7 days. On the final day, mice were given a final injection and the tibialis anterior muscle was harvested 6.5 hr later. RNA was extracted from the TA muscle and subjected to RNA sequencing analysis.