Toll-like receptor 4 mediates lipopolysaccharide-induced muscle catabolism via coordinate activation of ubiquitin-proteasome and autophagy-lysosome pathways
Toll-like receptor 4 mediates lipopolysaccharide-induced muscle catabolism via coordinate activation of ubiquitin-proteasome and autophagy-lysosome pathways
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DOI：
10.1096/fj.10-164152
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发表时间：
2011-01-01
期刊：
影响因子：
4.8
通讯作者：
Li, Yi-Ping
中科院分区：
文献类型：
--
作者：
Doyle, Alexander;Zhang, Guohua;Li, Yi-Ping
恶病质肌肉萎缩是许多炎症条件的常见并发症，主要是由于过度的肌肉分解代谢。然而，其发病机制和干预策略仍有待确定。在这里，我们验证了toll样受体4 （TLR4）是炎症性肌肉分解代谢的主要调节因子的假设。我们发现，脂多糖（LPS）激活TLR4通过上调自噬体的形成和泛素连接酶atrogin1 /MAFbx和MuRF1的表达诱导C2C12肌管萎缩。tlr4介导的p38 MAPK激活是atrogin1/MAFbx和自噬体上调导致肌管萎缩的必要和充分条件。同样，LPS上调小鼠肌肉自噬体的形成和泛素连接酶的表达。重要的是，自噬抑制剂3-甲基腺嘌呤完全消除脂多糖诱导的肌肉蛋白水解，而蛋白酶体抑制剂乳酸蛋白酶素部分阻断它。此外，TLR4敲除或p38 MAPK抑制可消除lps诱导的肌肉蛋白水解。因此，TLR4通过协同激活泛素-蛋白酶体和自噬-溶酶体途径介导lps诱导的肌肉分解代谢。-Doyle， A., Zhang， G., Abdel Fattah， E. A., Eissa， N. T., Li, y . p .toll样受体4通过协同激活泛素-蛋白酶体和自噬-溶酶体途径介导脂多糖诱导的肌肉分解代谢。中国生物医学工程学报（英文版），2011,33(2):444 - 444。www.fasebj.org
Cachectic muscle wasting is a frequent complication of many inflammatory conditions, due primarily to excessive muscle catabolism. However, the pathogenesis and intervention strategies against it remain to be established. Here, we tested the hypothesis that Toll-like receptor 4 (TLR4) is a master regulator of inflammatory muscle catabolism. We demonstrate that TLR4 activation by lipopolysaccharide (LPS) induces C2C12 myotube atrophy via up-regulating autophagosome formation and the expression of ubiquitin ligase atrogin-1/MAFbx and MuRF1. TLR4-mediated activation of p38 MAPK is necessary and sufficient for the up-regulation of atrogin1/MAFbx and autophagosomes, resulting in myotube atrophy. Similarly, LPS up-regulates muscle autophagosome formation and ubiquitin ligase expression in mice. Importantly, autophagy inhibitor 3-methyladenine completely abolishes LPS-induced muscle proteolysis, while proteasome inhibitor lactacystin partially blocks it. Furthermore, TLR4 knockout or p38 MAPK inhibition abolishes LPS-induced muscle proteolysis. Thus, TLR4 mediates LPS-induced muscle catabolism via coordinate activation of the ubiquitin-proteasome and the autophagy-lysosomal pathways.-Doyle, A., Zhang, G., Abdel Fattah, E. A., Eissa, N. T., Li, Y.-P. Toll-like receptor 4 mediates lipopolysaccharide-induced muscle catabolism via coordinate activation of ubiquitin-proteasome and autophagy-lysosome pathways. FASEB J. 25, 99-110 (2011). www.fasebj.org