An extract of Artemisia dracunculus L. inhibits ubiquitin-proteasome activity and preserves skeletal muscle mass in a murine model of diabetes.
An extract of Artemisia dracunculus L. inhibits ubiquitin-proteasome activity and preserves skeletal muscle mass in a murine model of diabetes.
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DOI：
10.1371/journal.pone.0057112
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Floyd ZE
中科院分区：
文献类型：
--
作者：
Kirk-Ballard H;Wang ZQ;Acharya P;Zhang XH;Yu Y;Kilroy G;Ribnicky D;Cefalu WT;Floyd ZE
胰岛素信号传导受损是2型糖尿病的一个关键特征，与骨骼肌中泛素-蛋白酶体依赖性蛋白降解增加有关。龙蒿提取物。（称为PMI 5011）通过增加骨骼肌中的胰岛素信号传导来改善胰岛素作用。我们试图确定PMI 5011对胰岛素信号传导的影响是否延伸到泛素-蛋白酶体系统的调节。使用C2 C12肌管和2型糖尿病的KK-Ay鼠模型来评估PMI 5011对泛素化的稳态水平、蛋白酶体活性和Atrogin-1和MuRF-1表达的影响，Atrogin-1和MuRF-1是随着受损的胰岛素信号传导而上调的肌肉特异性泛素连接酶。我们的研究结果表明，PMI 5011抑制蛋白酶体活性和稳态泛素化水平在体外和体内。PMI 5011的作用由PI 3 K/Akt信号传导介导，并且与Atrogin-1和MuRF-1的表达降低相关。在激素或脂肪酸诱导的胰岛素抵抗的体外条件下，PMI 5011改善胰岛素信号传导并降低Atrogin-1和MuRF-1蛋白水平。在2型糖尿病的KK-Ay鼠模型中，骨骼肌泛素化和蛋白酶体活性被抑制，Atrogin-1和MuRF-1表达被PMI 5011降低。PMI 5011介导的体内泛素-蛋白酶体系统的变化与Akt和FoxO 3a磷酸化的增加和肌纤维尺寸的增加相关。Atrogin-1和MuRF-1的表达，泛素-蛋白酶体活性和肌纤维大小的变化由PMI 5011在胰岛素抵抗的存在下调节表明植物提取物PMI 5011可能具有治疗潜力，在2型糖尿病的肌肉质量的保存。
Impaired insulin signaling is a key feature of type 2 diabetes and is associated with increased ubiquitin-proteasome-dependent protein degradation in skeletal muscle. An extract of Artemisia dracunculus L. (termed PMI5011) improves insulin action by increasing insulin signaling in skeletal muscle. We sought to determine if the effect of PMI5011 on insulin signaling extends to regulation of the ubiquitin-proteasome system. C2C12 myotubes and the KK-Ay murine model of type 2 diabetes were used to evaluate the effect of PMI5011 on steady-state levels of ubiquitylation, proteasome activity and expression of Atrogin-1 and MuRF-1, muscle-specific ubiquitin ligases that are upregulated with impaired insulin signaling. Our results show that PMI5011 inhibits proteasome activity and steady-state ubiquitylation levels in vitro and in vivo. The effect of PMI5011 is mediated by PI3K/Akt signaling and correlates with decreased expression of Atrogin-1 and MuRF-1. Under in vitro conditions of hormonal or fatty acid-induced insulin resistance, PMI5011 improves insulin signaling and reduces Atrogin-1 and MuRF-1 protein levels. In the KK-Ay murine model of type 2 diabetes, skeletal muscle ubiquitylation and proteasome activity is inhibited and Atrogin-1 and MuRF-1 expression is decreased by PMI5011. PMI5011-mediated changes in the ubiquitin-proteasome system in vivo correlate with increased phosphorylation of Akt and FoxO3a and increased myofiber size. The changes in Atrogin-1 and MuRF-1 expression, ubiquitin-proteasome activity and myofiber size modulated by PMI5011 in the presence of insulin resistance indicate the botanical extract PMI5011 may have therapeutic potential in the preservation of muscle mass in type 2 diabetes.
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