GSK-3β inhibitors reduce protein degradation in muscles from septic rats and in dexamethasone-treated myotubes
GSK-3β inhibitors reduce protein degradation in muscles from septic rats and in dexamethasone-treated myotubes
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DOI：
10.1016/j.biocel.2005.06.002
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发表时间：
2005-10-01
影响因子：
4
通讯作者：
Hasselgren, PO
中科院分区：
文献类型：
--
作者：
Evenson, AR;Fareed, MU;Hasselgren, PO
脓毒症与肌肉萎缩有关，主要反映肌肉蛋白水解作用增加。最近的研究表明，抑制 GSK-3 β 活性可能会抵消骨骼肌的分解代谢刺激。我们测试了以下假设：用 GSK-3 β 抑制剂 LiCl 和 TDZD-8 治疗脓毒症大鼠的肌肉会减少脓毒症引起的肌肉蛋白水解。由于败血症期间的肌肉萎缩至少部分是由糖皮质激素介导的，因此我们还测试了 GSK-3 β 抑制剂对地塞米松处理的培养肌管中蛋白质降解的影响。用 LiCl 或 TDZD-8 处理孵育的指长伸肌可降低基础和脓毒症诱导的蛋白质分解率。当培养的肌管用 LiCl 或 GSK-3 β 抑制剂 SB216763 或 SB415286 之一处理时，蛋白质降解减少。用LiCl处理培养的肌肉或培养的肌管，而不是其他GSK-3β抑制剂，导致GSK-3β在Ser9处的磷酸化增加，与激酶的失活一致，并表明本实验中使用的其他抑制剂通过磷酸化独立机制抑制GSK-30。目前的结果表明，GSK-3 β 抑制剂可用于预防或治疗脓毒症引起的、糖皮质激素调节的肌肉蛋白水解。 (c) 2005 Elsevier Ltd. 保留所有权利。
Sepsis is associated with muscle wasting, mainly reflecting increased muscle proteolysis. Recent studies suggest that inhibition of GSK-3 beta activity may counteract catabolic stimuli in skeletal muscle. We tested the hypothesis that treatment of muscles from septic rats with the GSK-3 beta inhibitors LiCl and TDZD-8 would reduce sepsis-induced muscle proteolysis. Because muscle wasting during sepsis is, at least in part, mediated by glucocorticoids, we also tested the effects of GSK-3 beta inhibitors on protein degradation in dexamethasone-treated cultured myotubes. Treatment of incubated extensor digitorum longus muscles with LiCl or TDZD-8-reduced basal and sepsis-induced protein breakdown rates. When cultured myotubes were treated with LiCl or one of the GSK-3 beta inhibitors SB216763 or SB415286, protein degradation was reduced. Treatment of incubated muscles or cultured myotubes with LiCl, but not the other GSK-3 beta inhibitors, resulted in increased phosphorylation of GSK-3 beta at Ser9, consistent with inactivation of the kinase and suggesting that the other inhibitors used in the present experiments inhibit GSK-30 by phosphorylation-independent mechanisms. The present results suggest that GSK-3 beta inhibitors may be used to prevent or treat sepsis-induced, glucocorticoid-regulated muscle proteolysis. (c) 2005 Elsevier Ltd. All rights reserved.