TY - JOUR
T1 - A cell-autonomous role for the glucocorticoid receptor in skeletal muscle atrophy induced by systemic glucocorticoid exposure
AU - Watson, Monica L.
AU - Baehr, Leslie M.
AU - Reichardt, Holger M.
AU - Tuckermann, Jan P.
AU - Bodine, Sue C.
AU - Furlow, John
PY - 2012/5/15
Y1 - 2012/5/15
N2 - 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 e3KO) using Cre-lox technology. In MGR e3KO 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 e3KO 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 e3KO 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 e3KO 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 e3KO mouse is a useful model for studying the role of the GR and its target genes in multiple skeletal muscle atrophy models.
AB - 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 e3KO) using Cre-lox technology. In MGR e3KO 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 e3KO 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 e3KO 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 e3KO 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 e3KO mouse is a useful model for studying the role of the GR and its target genes in multiple skeletal muscle atrophy models.
KW - Denervation
KW - Dexamethasone
KW - Muscle atrophy F-box
KW - Muscle RING finger 1
KW - Nutritional deprivation
UR - http://www.scopus.com/inward/record.url?scp=84861118898&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84861118898&partnerID=8YFLogxK
U2 - 10.1152/ajpendo.00512.2011
DO - 10.1152/ajpendo.00512.2011
M3 - Article
C2 - 22354783
AN - SCOPUS:84861118898
VL - 302
JO - American Journal of Physiology - Renal Fluid and Electrolyte Physiology
JF - American Journal of Physiology - Renal Fluid and Electrolyte Physiology
SN - 1931-857X
IS - 10
ER -