title: 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.
authors.affiliation: Dept. of Neurobiology, Physiology, and Behavior, Univ. of California, One Shields Ave., Davis, CA 95616-8519, USA.
authors.forename: Monica L
authors.initials: ML
authors.lastname: Watson
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Baehr
authors.forename: Holger M
authors.initials: HM
authors.lastname: Reichardt
authors.forename: Jan P
authors.initials: JP
authors.lastname: Tuckermann
authors.forename: Sue C
authors.initials: SC
authors.lastname: Bodine
authors.forename: J David
authors.initials: JD
authors.lastname: Furlow
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D031204:Caloric Restriction; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D003907:Dexamethasone / Q000494:pharmacology*; D039642:Eukaryotic Initiation Factors; D005938:Glucocorticoids / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009121:Muscle Denervation; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology*; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D005938:Glucocorticoids; D009124:Muscle Proteins; D010750:Phosphoproteins; D011965:Receptors, Glucocorticoid; D000070584:Tripartite Motif Proteins; D003907:Dexamethasone; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases