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Modeling Circadian Rhythms of Glucocorticoid Receptor and Glutamine Synthetase Expression in Rat Skeletal Muscle

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Purpose

The circadian rhythm of endogenous corticosterone (CS) may produce fluctuations of downstream gene expression in normal rats. This study examined changes in glucocorticoid receptor (GR) and glutamine synthetase (GS) expression in rat skeletal muscle in relation to plasma CS over a 24-h period.

Methods

Fifty-four normal male Wistar rats were sacrificed at 18 time points (n = 3) over 24 h. Plasma CS concentrations and gastrocnemius muscle GR and GS mRNA and GS activity were measured.

Results

The circadian rhythm of plasma CS was captured by a two-harmonic function. The expression of GR and GS mRNA and GS activity follow a circadian rhythm in normal rat skeletal muscle. GR mRNA reaches a trough at 4 h after the peak of plasma CS and it fluctuates between 0.55 and 0.9 fmol g tissue−1. GS mRNA and activity reach peaks at 6 and 12 h after the endogenous CS peak. GS mRNA oscillates between 3 and 6 fmol g tissue−1, whereas GS activity fluctuates between 17 and 23 μmol min−1 g protein−1. Mechanistic receptor/gene-mediated pharmacodynamic models were applied to describe the temporal patterns of GR mRNA, GS mRNA, and GS activity within the circadian cycle.

Conclusions

The integrated models were able to capture the circadian expression patterns of plasma CS, and GR and GS in normal rat skeletal muscle showing a dependence of tissue gene expression on plasma CS.

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Abbreviations

ADX:

adrenalectomized

CBG:

corticosteroid binding globulin

CS:

corticosterone

DR:

drug–receptor complex

GR:

glucocorticoid receptor

GRE:

glucocorticoid response element

GRG:

glucose repressible gene

GS:

glutamine synthetase

HPA:

hypothalamus–pituitary–adrenal axis

PK/PD:

pharmacokinetic/pharmacodynamic

QSPR:

quantitative structure–property relationship

RT-PCR:

reverse transcription–polymerase chain reaction

TAT:

tyrosine aminotransferase

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Acknowledgments

The authors would like to thank Dr. Donald E. Mager and Ms. Nancy A. Pyszczynski for performance of animal studies and Ms. Suzette M. Mis for HPLC analysis. We would also like to thank Dr. Lori Badura from Pfizer Inc. for her advice in the experimental design. This study was supported by grant GM 24211 from the National Institutes of Health and by a research grant from NASA.

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Correspondence to William J. Jusko.

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Yao, Z., DuBois, D.C., Almon, R.R. et al. Modeling Circadian Rhythms of Glucocorticoid Receptor and Glutamine Synthetase Expression in Rat Skeletal Muscle. Pharm Res 23, 670–679 (2006). https://doi.org/10.1007/s11095-005-9608-3

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  • DOI: https://doi.org/10.1007/s11095-005-9608-3

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