title: REDD1 (regulated in development and DNA damage response 1) expression in skeletal muscle as a surrogate biomarker of the efficiency of glucocorticoid receptor blockade.
abstract: Glucocorticoids are potent regulators of cell metabolism, and in part act through a receptor-based mechanism to alter the transcription of target genes. A plethora of studies have utilized the glucocorticoid receptor antagonist, RU-486, both in vivo and in vitro, to reverse or prevent hormone-induced alterations in gene transcription. However, although RU-486 potently blocks many of the functions of the receptor, it does not lower plasma concentrations of the hormone, and a biomarker for the effectiveness of RU-486 in blocking receptor activation is lacking. In the present study, we demonstrate glucocorticoid-induced changes in expression of a protein referred to as regulated in development and DNA damage response (REDD1) in a variety of mouse models of hypercortisolemia including stroke, type 2 diabetes, and stress induced by confinement. Notably REDD1 expression in skeletal muscle positively correlated with changes in corticosterone concentrations in all conditions. RU-486 had no effect on corticosterone concentrations, but strongly attenuated the stroke-, diabetes-, and stress-induced changes in REDD1 expression. Overall, the results of the present study suggest that changes in REDD1 expression in skeletal muscle represent an excellent surrogate biomarker for the efficacy of RU-486 treatment in repressing glucocorticoid action.
authors.affiliation: Department of Neural & Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kumari
authors.forename: Lisa B
authors.initials: LB
authors.lastname: Willing
authors.forename: Leonard S
authors.initials: LS
authors.lastname: Jefferson
authors.forename: Ian A
authors.initials: IA
authors.lastname: Simpson
authors.forename: Scot R
authors.initials: SR
authors.lastname: Kimball
mesh_terms: D000818:Animals; D054316:Biomarkers, Pharmacological / Q000378:metabolism*; D004249:DNA Damage; D005938:Glucocorticoids / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D054316:Biomarkers, Pharmacological; C469992:Ddit4 protein, mouse; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D015735:Mifepristone