Protection against dexamethasone-induced muscle atrophy is related to modulation by testosterone of FOXO1 and PGC-1α

Glucocorticoid-induced muscle atrophy results from muscle protein catabolism and reduced protein synthesis, associated with increased expression of two muscle-specific ubiquitin ligases (MAFbx and MuRF1), and of two inhibitors of protein synthesis, REDD1 and 4EBP1. MAFbx, MuRF1, REDD1 and 4EBP1 are up-regulated by the transcription factors FOXO1 and FOXO3A. The transcriptional co-activator PGC-1α has been shown to attenuate many forms of muscle atrophy and to repress FOXO3A-mediated transcription of atrophy-specific genes. Dexamethasone-induced muscle atrophy can be prevented by testosterone, which blocks up-regulation by dexamethasone of FOXO1. Here, an animal model of dexamethasone-induced muscle atrophy was used to further characterize effects of testosterone to abrogate adverse actions of dexamethasone on FOXO1 levels and nuclear localization, and to determine how these agents affect PGC-1α, and its upstream activators, p38 MAPK and AMPK. In rat gastrocnemius muscle, testosterone blunted the dexamethasone-mediated increase in levels of FOXO1 mRNA, and FOXO1 total and nuclear protein. Dexamethasone reduced total and nuclear PGC-1α protein levels in the gastrocnemius; co-administration of testosterone with dexamethasone increased total and nuclear PGC-1α levels above those present in untreated controls. Testosterone blocked dexamethasone-induced decreases in activity of p38 MAPK in the gastrocnemius muscle. Regulation of FOXO1, PGC-1α and p38 MAPK by testosterone may represent a novel mechanism by which this agent protects against dexamethasone-induced muscle atrophy.

Research highlights
► In rat gastrocnemius muscle, dexamethasone reduced PGC-1α cellular and nuclear levels without altering mRNA levels for this factor.
► Dexamethasone reduced phosphorylating of p38 MAPK, which stabilizes PGC-1α and promotes its nuclear entry.
► Co-administration of testosterone with dexamethasone increased cellular and nuclear levels of PGC-1α protein without changing its mRNA levels.
► Co-administration of testosterone restored p38 MAPK levels to those of controls.