Description:
Glucocorticoids (GCs) are important regulators of skeletal muscle mass and exert their actions primarily via GC receptors (GR) that interact with GC response elements (GREs) near target genes. However, many GR target genes lack clear GREs and there may be nongenomic effects of GCs. In addition, actions of GCs on skeletal muscle mass and function may be exerted outside the myotubes themselves. To investigate skeletal muscle transcriptional responses to GCs leading to atrophy and metabolic changes, we examined the dexamethasone (DEX) induced gene expression in two mouse lines: 1. GR dimerization mutant mice (GRdim) that ubiquitously express GR with an impaired ability to dimerize at certain GREs and 2. muscle specific GR knockout mice (muGRKO). Induction of the muscle atrophy associated MuRF1 gene is blunted in GRdim mice but fully prevented in muGRKO mice; induction of another important atrophy gene, MAFbx, is unaffected in GRdim mice but is also completely blocked in muGRKO mice. In both models, extracellular matrix genes like collagen 1A1 are repressed by DEX, as expected. We hypothesize that the skeletal muscle GR is important for mediating high dose GC induced atrophy, however the deleterious effects of GCs in muscle structure and function may not be muscle cell autonomous. The GRdim and muGRKO mice will be useful models to determine the importance of the GR and its target genes in several muscle atrophy models. This work was funded by NIH RO1 DK75801 and NIH Training Grant 2T32GM007377‐31A1.