p38 MAPK links oxidative stress to autophagy-related gene expression in cachectic muscle wasting
p38 MAPK links oxidative stress to autophagy-related gene expression in cachectic muscle wasting
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DOI：
10.1152/ajpcell.00192.2009
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发表时间：
2010-03-01
影响因子：
5.5
通讯作者：
Yan, Z.
中科院分区：
文献类型：
--
作者：
McClung, J. M.;Judge, A. R.;Yan, Z.
P38MAPK将氧化应激与恶病质肌肉萎缩的自噬相关基因表达联系起来。Am J Physiol Cell Physiol 298：C542-C549,2010。首次发表于2009年12月2日；doi：10.1152/ajpcell.00192.2009。-氧化应激是恶病质肌肉损耗的主要触发因素，但将其与肌肉损耗过程联系起来的信号通路(S)仍未确定。在这里，我们报告了小鼠骨骼肌中p38丝裂原活化蛋白激酶(MAPK)的激活(磷酸化)和氧化应激(反式-4-羟基-2-壬烯醛蛋白修饰)的增加，在小鼠体内注射脂多糖(1 mg/kg)后8h和地塞米松(25 mg/kg)注射后24h，同时自噬相关基因ATG6、ATG7和ATG12上调。用氧化剂过氧化氢处理培养的C2C12肌管4h后，p38磷酸化增加，FOXO_3磷酸化降低，ATG7基因表达增强，但不激活核因子-kappaB或FOXO3a转录活性。此外，SB202190抑制p38α/β可以阻止过氧化氢诱导的萎缩，减少ATG7和萎缩基因[肌萎缩F-box蛋白(MAFbx/Atrogin-1)、肌肉环指蛋白1(Murf-1)和Nedd4]的上调。这些发现为p38α/βMAPK在介导氧化应激诱导的自噬相关基因中的作用提供了直接证据，表明p38α/βMAPK调节肌肉萎缩中的泛素蛋白酶体和自噬溶酶体系统。
McClung JM, Judge AR, Powers SK, Yan Z. p38 MAPK links oxidative stress to autophagy-related gene expression in cachectic muscle wasting. Am J Physiol Cell Physiol 298: C542-C549, 2010. First published December 2, 2009; doi: 10.1152/ajpcell.00192.2009.-Oxidative stress is a primary trigger of cachectic muscle wasting, but the signaling pathway(s) that links it to the muscle wasting processes remains to be defined. Here, we report that activation of p38 mitogen-activated protein kinase (MAPK) (phosphorylation) and increased oxidative stress (trans-4-hydroxy-2-nonenal protein modification) in skeletal muscle occur as early as 8 h after lipopolysaccharide (1 mg/kg) and 24 h after dexamethasone (25 mg/kg) injection (intraperitoneal) in mice, concurrent with upregulation of autophagy-related genes, Atg6, Atg7, and Atg12. Treating cultured C2C12 myotubes with oxidant hydrogen peroxide (4 h) resulted in increased p38 phosphorylation and reduced FoxO3 phosphorylation along with induced Atg7 mRNA expression without activation of NF-kappa B or FoxO3a transcriptional activities. Furthermore, inhibition of p38 alpha/beta by SB202190 blocked hydrogen peroxide-induced atrophy with diminished upregulation of Atg7 and atrogenes [muscle atrophy F-box protein (MAFbx/Atrogin-1), muscle ring finger protein 1 (MuRF-1), and Nedd4]. These findings provide direct evidence for p38 alpha/beta MAPK in mediating oxidative stress-induced autophagy-related genes, suggesting that p38 alpha/beta MAPK regulates both the ubiquitin-proteasome and the autophagylysosome systems in muscle wasting.