Microarray analysis of the temporal response of skeletal muscle to methylprednisolone: comparative analysis of two dosing regimens

Abstract

Ϫ1 ⅐ h Ϫ1 methylprednisolone for up to 7 days via subcutaneously implanted minipumps. Four control and forty drug-treated animals were killed at ten different time points during infusion. Liver total RNAs were hybridized to 44 individual Affymetrix REA230A gene chips. Previously, we described a filtration approach for identifying genes of interest in microarray data sets developed from tissues of rats treated with methylprednisolone (MPL) following acute dosing. Here, a similar approach involving a series of three filters was applied sequentially to identify genes of interest. These filters were designed to eliminate probe sets that were not expressed in the tissue, not regulated by the drug, or did not meet defined quality control standards. Filtering eliminated 86% of probe sets, leaving a remainder of 2,316 for further consideration. In a previous study, 653 probe sets were identified as MPL regulated following administration of a single (acute) dose of the drug. Comparison of the two data sets yielded 196 genes identified as regulated by MPL in both dosing regimens. Because of receptor downregulation, it was predicted that genes regulated by receptor-glucocorticoid response element interactions would exhibit tolerance in chronic profiles. However, many genes did not exhibit steroid tolerance, indicating that present perspectives on the mechanism of glucocorticoid action cannot entirely explain all temporal profiles.

The glucocorticoid receptor and FOXO1 synergistically activate the skeletal muscle atrophy-associated MuRF1 gene

“…Consequently, the residual level of MuRF1 expression in GR dim mice may well be enough to support full DEX-induced atrophy. The rapid rise and gradual decline of MuRF1 expression we observed in DEX-treated Balb/c mice is in agreement with experiments in rats dosed with the synthetic glucocorticoid prednisolone (1). Concerning the mechanism of residual MuRF1 induction in GR dim mice, it is conspicuous that cotransfection of FOXO1 with the homodimerization mutant GR supports at least modest induction of the MuRF1 promoter in transient transfection assays, whereas the induction without FOXO1 is completely lost (Fig.…”

Tandem Analysis of Transcriptome and Proteome Changes after a Single Dose of Corticosteroid: A Systems Approach to Liver Function in Pharmacogenomics

“…Previously we used Affymetrix gene chips to profile temporal changes in mRNA expression in multiple tissues following CS administration in rats 2007a;2007b). These studies characterized global dynamics of the system that are regulated by CS at the transcriptional level.…”

Ligand-based gene expression profiling reveals novel roles of glucocorticoid receptor in cardiac metabolism

“…Taking into account that circulating cortisol/COR levels are at least 100-fold higher than those of ALD, and that MR has the same affinity for ALD and glucocorticoids, MR, as well as GR, may be permanently occupied by glucocorticoids, and glucocorticoid effects could be mediated by both GR and MR (48). The recent advent of microarray and other technologies has facilitated the identification of a number of glucocorticoid-regulated genes (1,20,34,36,45), and it becomes apparent that the profile of those glucocorticoid-target genes differs according to the cell types and the mode of interaction with ligands (49). However, because of the redundancy of the ligand-receptor interaction, not a single study could clearly differentiate target genes for cardiac GR and MR.…”