Atractylenolide III Attenuates Muscle Wasting in Chronic Kidney Disease via the Oxidative Stress-Mediated PI3K/AKT/mTOR Pathway
Atractylenolide III Attenuates Muscle Wasting in Chronic Kidney Disease via the Oxidative Stress-Mediated PI3K/AKT/mTOR Pathway
复制标题
白术内酯 III 通过氧化应激介导的 PI3K/AKT/mTOR 途径减轻慢性肾病中的肌肉萎缩
DOI：
10.1155/2019/1875471
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发表时间：
2019-01-01
影响因子：
--
通讯作者：
Wei, Lianbo
中科院分区：
文献类型：
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作者：
Wang, Mingqing;Hu, Rong;Wei, Lianbo
氧化应激导致晚期慢性肾脏病(CKD)患者肌肉萎缩。苍术内酯III(ATL-III)是苍术的主要活性成分，此前已被报道具有抗氧化剂的功能。本研究旨在探讨ATL-III是否通过减轻氧化应激对CKD诱导的肌肉萎缩具有保护作用。结果表明，与5/6肾切除(5/6 NX)模型组相比，ATL-III治疗组大鼠血清肌酐(Scr)、尿素氮(BUN)和尿蛋白水平明显降低，但高于假手术组。与5/6NX模型组相比，ATL-III组小鼠骨骼肌重增加，炎症减轻。与5/6 NX模型大鼠相比，ATL-III治疗组大鼠骨骼肌和血清中线粒体扩张程度减轻，CAT、GSH-Px和SOD活性升高，MDA水平降低，提示ATL-III可减轻线粒体损伤，提高抗氧化酶活性，从而减少ROS的产生。此外，在透射电子显微镜下，ATL-III处理的大鼠腓肠肌中累积的自噬小体(AP)和自溶酶体(ALS)减少，Western blotting显示Lc3-II表达下调，p62表达上调。这一证据表明，ATL-III改善了CKD大鼠骨骼肌萎缩，减轻了氧化应激和自噬。此外，ATL-III还能增加CKD大鼠骨骼肌中p-PI3K、p-AKT和p-mTOR的蛋白水平。为了进一步揭示相关机制，我们对氧化应激介导的PI3K/AKT/mTOR通路进行了研究，结果表明，ATL-III可上调肿瘤坏死因子-α诱导的C2C12成肌细胞中p-PI3K、p-AKT和p-mTOR的表达，但过表达NOX2以增加ROS产生后，其抑制作用被逆转。我们的发现表明，ATL-III是一种潜在的保护性药物，通过激活氧化应激介导的PI3K/AKT/mTOR途径来防止肌肉萎缩。
Oxidative stress contributes to muscle wasting in advanced chronic kidney disease (CKD) patients. Atractylenolide III (ATL-III), the major active constituent of Atractylodes rhizome, has been previously reported to function as an antioxidant. This study is aimed at investigating whether ATL-III has protective effects against CKD-induced muscle wasting by alleviating oxidative stress. The results showed that the levels of serum creatinine (SCr), blood urea nitrogen (BUN), and urinary protein significantly decreased in the ATL-III treatment group compared with the 5/6 nephrectomy (5/6 Nx) model group but were higher than those in the sham operation group. Skeletal muscle weight was increased, while inflammation was alleviated in the ATL-III administration group compared with the 5/6 Nx model group. ATL-III-treated rats also showed reduced dilation of the mitochondria, increased CAT, GSH-Px, and SOD activity, and decreased levels of MDA both in skeletal muscles and serum compared with 5/6 Nx model rats, suggesting that ATL-III alleviated mitochondrial damage and increased the activity of antioxidant enzymes, thus reducing the production of ROS. Furthermore, accumulated autophagosomes (APs) and autolysosomes (ALs) were reduced in the gastrocnemius (Gastroc) muscles of ATL-III-treated rats under transmission electron microscopy (TEM) together with the downregulation of LC3-II and upregulation of p62 according to Western blotting. This evidence indicated that ATL-III improved skeletal muscle atrophy and alleviated oxidative stress and autophagy in CKD rats. Furthermore, ATL-III could also increase the protein levels of p-PI3K, p-AKT, and p-mTOR in skeletal muscles in CKD rats. To further reveal the relevant mechanism, the oxidative stress-mediated PI3K/AKT/mTOR pathway was assessed, which showed that a reduced expression of p-PI3K, p-AKT, and p-mTOR in C2C12 myoblast atrophy induced by TNF-α could be upregulated by ATL-III; however, after the overexpression of Nox2 to increase ROS production, the attenuated effect was reversed. Our findings indicated that ATL-III is a potentially protective drug against muscle wasting via activation of the oxidative stress-mediated PI3K/AKT/mTOR pathway.