Yao Zhenling, DuBois Debra C, Almon Richard R, Jusko William J
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, 565 Hochstetter Hall, Buffalo, New York 14260, USA.
Pharm Res. 2006 Apr;23(4):670-9. doi: 10.1007/s11095-005-9608-3. Epub 2006 Feb 2.
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.
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.
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 micromol 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.
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.
内源性皮质酮（CS）的昼夜节律可能导致正常大鼠下游基因表达的波动。本研究检测了24小时内大鼠骨骼肌中糖皮质激素受体（GR）和谷氨酰胺合成酶（GS）表达相对于血浆CS的变化。
54只正常雄性Wistar大鼠在24小时内的18个时间点（n = 3）被处死。测量血浆CS浓度、腓肠肌GR和GS mRNA以及GS活性。
血浆CS的昼夜节律由双谐波函数捕获。正常大鼠骨骼肌中GR和GS mRNA的表达以及GS活性遵循昼夜节律。GR mRNA在血浆CS峰值后4小时达到谷值，其在0.55至0.9 fmol g组织（-1）之间波动。GS mRNA和活性在内源性CS峰值后6小时和12小时达到峰值。GS mRNA在3至6 fmol g组织（-1）之间振荡，而GS活性在17至23 μmol min（-1）g蛋白（-1）之间波动。应用机制性受体/基因介导的药效学模型来描述昼夜周期内GR mRNA、GS mRNA和GS活性的时间模式。
整合模型能够捕获正常大鼠骨骼肌中血浆CS、GR和GS的昼夜表达模式，表明组织基因表达对血浆CS的依赖性。
