Dosing schedule-dependent attenuation of dexamethasone-induced muscle atrophy in mice
Dosing schedule-dependent attenuation of dexamethasone-induced muscle atrophy in mice
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DOI：
10.3109/07420528.2013.872654
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发表时间：
2014-01-01
影响因子：
2.8
通讯作者：
Oishi, Katsutaka
中科院分区：
文献类型：
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作者：
Nakao, Reiko;Yamamoto, Saori;Oishi, Katsutaka
许多炎症和自身免疫性疾病使用合成糖皮质激素治疗。然而，过量的糖皮质激素往往会导致不可预测的影响，包括肌肉萎缩。内源性糖皮质激素水平以昼夜节律的方式强烈波动，并在人类和夜间啮齿动物的活动期开始前达到峰值。本研究确定外源性糖皮质激素诱导的肌肉萎缩是否可以通过优化给药时间来避免。我们在对应于内源性糖皮质激素水平的峰值（清晨）或谷值（清晨）的时间向小鼠施用单次每日剂量的糖皮质激素类似物地塞米松（Dex），持续10天。内源性糖皮质激素的顶相给药显著减弱了右旋糖酐诱导的腓肠肌（Ga）和胫骨前肌（TA）肌肉（主要包括快缩肌纤维）的消耗。实时RT-PCR显示，Dex诱导的Ga和TA肌肉中编码萎缩相关泛素连接酶Muscle Atrophy F-box（Fbxo 32，也称为MAFbx/Atrogin-1）和Muscle RING finger 1（Trim 63，也称为MuRF 1）的基因的mRNA表达在夜间给药时显著减弱。Dex对比目鱼肌（So）的重量影响可忽略不计，比目鱼肌主要包括慢缩肌纤维，但在两个给药时间显著且相似地降低了脾脏的重量。这些结果表明，糖皮质激素诱导的肌肉萎缩可以通过优化给药方案来减弱。
Many inflammatory and autoimmune diseases are treated using synthetic glucocorticoids. However, excessive glucocorticoid can often cause unpredictable effects including muscle atrophy. Endogenous glucocorticoid levels robustly fluctuate in a circadian manner and peak just before the onset of the active phase in both humans and nocturnal rodents. The present study determines whether muscle atrophy induced by exogenous glucocorticoid can be avoided by optimizing dosing times. We administered single daily doses of the glucocorticoid analog dexamethasone (Dex) to mice for 10 days at the times of day corresponding to peak (early night) or trough (early morning) endogenous glucocorticoid levels. Administration at the acrophase of endogenous glucocorticoids significantly attenuated Dex-induced wasting of the gastrocnemius (Ga) and tibialis anterior (TA) muscles that comprise mostly fast-twitch muscle fibers. Real-time RT-PCR revealed that the Dex-induced mRNA expression of genes encoding the atrophy-related ubiquitin ligases Muscle Atrophy F-box (Fbxo32, also known as MAFbx/Atrogin-1) and Muscle RING finger 1 (Trim63, also known as MuRF1) in the Ga and TA muscles was significantly attenuated by Dex when administered during the early night. Dex negligibly affected the weight of the soleus (So) muscle that mostly comprises slow-twitch muscle fibers, but significantly and similarly decreased the weight of the spleen at both dosing times. These results suggest that glucocorticoid-induced muscle atrophy can be attenuated by optimizing the dosing schedule.