Mechanism of attenuation of muscle protein degradation induced by tumor necrosis factor-α and angiotensin II by β-hydroxy-β-methylbutyrate
Mechanism of attenuation of muscle protein degradation induced by tumor necrosis factor-α and angiotensin II by β-hydroxy-β-methylbutyrate
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DOI：
10.1152/ajpendo.90567.2008
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发表时间：
2008-12-01
影响因子：
5.1
通讯作者：
Tisdale, Michael J.
中科院分区：
文献类型：
--
作者：
Eley, Helen L.;Russell, Steven T.;Tisdale, Michael J.
Eley HL，Russell ST，Tisdale MJ.β-羟基-β-甲基丁酸酯减弱肿瘤坏死因子-α和血管紧张素II诱导的肌肉蛋白降解的机制。Am J Physiol Endocrinol Metab 295：E1417-E1426，2008.首次发表于2008年10月7日; doi：10.1152/ajpendo.90567.2008。- 肿瘤坏死因子-α（TNF-alpha）/干扰素-γ（IFN-gamma）和血管紧张素II（ANG II）均诱导小鼠肌管总蛋白降解增加，而β-羟基-β-甲基丁酸酯（HMB; 50 μ M）处理可完全减弱这种降解。在30分钟内活性氧（ROS）的形成增加，以及caspase-3和-8的活性增加，这两种作用都被HMB减弱。此外，caspase-3和-8的抑制剂完全减弱了TNF-α/IFN-γ和ANG II诱导的ROS形成和总蛋白降解。双链RNA依赖性蛋白激酶（PKR）的自磷酸化增加，特异性caspase-3和-8抑制剂可减弱PKR的自磷酸化。与表达野生型PKR的肌管相比，表达无催化活性的PKR变体PKR Delta 6的肌管对TNF-α/IFN-γ的反应既不形成ROS，也不发生蛋白质降解，尽管仍有半胱天冬酶-3和-8的活化。HMB还减弱PKR的活化，表明其在蛋白质降解中是重要的。ROS的形成减弱鱼藤酮，线粒体电子传递链的抑制剂，硝基-L-精氨酸甲酯，一氧化氮合酶的抑制剂，和SB 203580，p38丝裂原活化蛋白激酶（p38 MAPK）的特异性抑制剂，这也减弱总蛋白质降解。PKR对p38 MAPK的激活提供了与ROS形成的联系。这些结果表明，TNF-α/IFN-γ和ANG II通过一个共同的信号传导途径诱导肌肉蛋白降解，该途径被HMB减弱，并且这涉及胱天蛋白酶-3和-8的初始活化，随后是PKR的自磷酸化和活化，然后通过p38 MAPK的活化导致ROS形成增加。已知增加的ROS形成通过泛素-蛋白酶体途径诱导蛋白质降解。
Eley HL, Russell ST, Tisdale MJ. Mechanism of attenuation of muscle protein degradation induced by tumor necrosis factor-alpha and angiotensin II by beta-hydroxy-beta-methylbutyrate. Am J Physiol Endocrinol Metab 295: E1417-E1426, 2008. First published October 7, 2008; doi: 10.1152/ajpendo.90567.2008. - Both tumor necrosis factor-alpha (TNF-alpha)/interferon-gamma (IFN-gamma) and angiotensin II (ANG II) induced an increase in total protein degradation in murine myotubes, which was completely attenuated by treatment with beta-hydroxy-beta-methylbutyrate (HMB; 50 mu M). There was an increase in formation of reactive oxygen species (ROS) within 30 min, as well as an increase in the activity of both caspase-3 and -8, and both effects were attenuated by HMB. Moreover, inhibitors of caspase-3 and -8 completely attenuated both ROS formation and total protein degradation induced by TNF-alpha/IFN-gamma and ANG II. There was an increased autophosphorylation of double-stranded RNA-dependent protein kinase (PKR), which was attenuated by the specific caspase-3 and -8 inhibitors. Neither ROS formation or protein degradation occurred in myotubes expressing a catalytically inactive PKR variant, PKR Delta 6, in response to TNF-alpha/IFN-gamma, compared with myotubes expressing wildtype PKR, although there was still activation of caspase-3 and -8. HMB also attenuated activation of PKR, suggesting that it was important in protein degradation. Formation of ROS was attenuated by rotenone, an inhibitor of the mitochondrial electron transport chain, nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase, and SB 203580, a specific inhibitor of p38 mitogen-activated protein kinase (p38 MAPK), which also attenuated total protein degradation. Activation of p38 MAPK by PKR provides the link to ROS formation. These results suggest that TNF-alpha/IFN-gamma and ANG II induce muscle protein degradation by a common signaling pathway, which is attenuated by HMB, and that this involves the initial activation of caspase-3 and -8, followed by autophosphorylation and activation of PKR, which then leads to increased ROS formation via activation of p38 MAPK. Increased ROS formation is known to induce protein degradation through the ubiquitin-proteasome pathway.