A cell-autonomous role for the glucocorticoid receptor in skeletal muscle atrophy induced by systemic glucocorticoid exposure

Abstract

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 (MGR(e3)KO) using Cre-lox technology. In MGR(e3)KO 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 eliminated completely in the MGR(e3)KO 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 MGR(e3)KO mice. In response to sciatic nerve lesion and hindlimb muscle denervation, muscle atrophy and upregulation of MuRF1 and MAFbx occurred to the same extent in both wild-type and MGR(e3)KO mice, indicating that a functional GR is not required to induce atrophy under these conditions. Therefore, we demonstrate conclusively 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 MGR(e3)KO mouse is a useful model for studying the role of the GR and its target genes in multiple skeletal muscle atrophy models.

Glucocorticoids and Skeletal Muscle

“…Interestingly, expression of a mutant GR that lacks the ability to translocate to the nucleus upon ligand binding in the MGRKO background at least partially rescues the atrophy and MAFbx/atrogin-1 induction in the diabetes model. Their data support a two step model for glucocorticoid induced atrophy in response to induced diabetes and starvation [ 144 ]: namely, insulin signaling must decrease or be otherwise impaired in order for the ligand activated GR to effectively further reduce PI3 kinase activity via a cytoplasmic interaction and activate KO mice nor was atrophy induced gene expression altered, demonstrating that the GR is not uniformly required for all conditions resulting in atrophy and it may be restricted to catabolic states [ 161 ]. These studies followed from prior work with a dimerization mutant GR expressing mouse line that surprisingly did not prevent excess glucocorticoid induced muscle atrophy, despite the presence of a near perfect palindromic GRE in the MuRF1 promoter [ 134 ].…”

Chronic stress alters concentrations of corticosterone receptors in a tissue-specific manner in wild house sparrows (Passer domesticus)

“…CORT both increases proteolysis and inhibits protein synthesis, freeing up amino acids to be used as substrates for gluconeogenesis (Hasselgren, 1999;Sapolsky et al, 2000). Because of this catabolic role, exogenous CORT administered through diet, implants or injections typically causes muscle wasting (Busch et al, 2008; Gray et al, 1990;Hull et al, 2007;Tomas et al, 1979); in mammals, this muscle-wasting effect is mediated by GR (Watson et al, 2012). Increased muscle receptor density in response to chronic stress, perhaps as part of a shift towards protein as an energy source, could help explain why muscle wasting occurs in these studies.…”

Animal Models of Altered Glucocorticoid Signaling

“…Muscle specifi c GR KO mice were completely protected from dexamethasone mediated muscle atrophy [ 37 ] indicating this is a cell autonomous process. Induction of the atrogins MURF1 and MAFbx1 was abrogated in muscle specifi c GR KO mice treated with glucocorticoid.…”