Glucocorticoids (GCs) are important regulators of skeletal muscle mass and prolonged exposure will induce significant muscle atrophy. To better understand the mechanism of skeletal muscle atrophy induced by elevated GC levels we examined three different models: exogenous synthetic GC treatment (dexamethasone, DEX), nutritional deprivation, and denervation. Specifically, we tested the direct contribution of the glucocorticoid receptor (GR) in skeletal muscle atrophy by creating a muscle specific GR knockout mouse line (MGRe3KO) using Cre-lox technology. In MGRe3KO mice, we found that the GR is essential for muscle atrophy in response to high dose DEX treatment. In addition, DEX regulation of multiple genes, including two important atrophy markers MuRF1 and MAFbx, is completely eliminated in the MGRe3KO mice. In a condition where endogenous GCs are elevated, such as nutritional deprivation, induction of MuRF1 and MAFbx was inhibited, but not completely blocked, in MGRe3KO mice. In response to sciatic nerve lesion and hindlimb muscle denervation, muscle atrophy and up-regulation of MuRF1 and MAFbx occurred to the same extent in both wild type and MGRe3KO mice, indicating that a functional GR is not required to induce atrophy under these conditions. Therefore, we conclusively demonstrate that the GR is an important mediator of skeletal muscle atrophy and associated gene expression in response to exogenous synthetic GCs in vivo, and that the MGRe3KO mouse is a useful model for studying the role of the GR and its target genes in multiple skeletal muscle atrophy models.
- nutritional deprivation
- Copyright © 2012, American Journal of Physiology - Endocrinology and Metabolism