Regulation of ubiquitin-proteasome and autophagy pathways after acute LPS and epoxomicin administration in mice.
Regulation of ubiquitin-proteasome and autophagy pathways after acute LPS and epoxomicin administration in mice.
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DOI：
10.1186/1471-2474-15-166
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发表时间：
2014-05-22
影响因子：
2.3
通讯作者：
Francaux M
中科院分区：
文献类型：
--
作者：
Jamart C;Gomes AV;Dewey S;Deldicque L;Raymackers JM;Francaux M
泛素-蛋白酶体途径(UPP)是脓毒症时被激活的一种主要的蛋白质降解途径，已被认为是预防恶病质引起的骨骼肌丢失的治疗靶点。尽管已有几项研究研究了蛋白酶体活性对内毒素注射的调节作用，但还没有一项研究将UPP对内毒素注射的整体反应定性为蛋白酶体被抑制的命运。在此，我们通过检测20S和26S蛋白酶体的β1、β2和β5的三种活性、稳态多泛素化蛋白水平、肌肉连接酶的基因水平以及调节UPP的信号通路，确定了内毒素血症(7.5m g/kg-8h)小鼠腓肠肌UPP主要关键成分的调制模式。另一个目标是评估一种特定的蛋白酶体抑制剂(环氧米星，0.5 mg/kg)对脓毒症UPP反应的影响。内毒素血症的急性期降低了气体/体重比，增加了MuRF1和MAFbx的mRNA，同时激活了已知的调节它们表达的途径。出乎意料的是，我们观察到在GAS中测得的所有20S和26S蛋白酶体活性都下降了，这可能与氧化应激有关，因为氧化蛋白(羰基水平)随着内毒素的增加而增加。环氧米星显著抑制心脏和肝脏中20S和26S蛋白酶体β5的活性，但不降低GAS中的蛋白酶体活性。然而，肌肉连接酶MuRF1和MAFbx的mRNA表达增加被部分挽救，而不影响其他已研究的信号通路。脂多糖还强烈激活自噬，这可以解释观察到的GAS萎缩和内毒素诱导的蛋白酶体活性降低的原因。我们的结果表明，在脂多糖诱导的肌肉萎缩的早期，UPP的调节是相反的，表现为蛋白酶体活性降低和肌肉特异性连接酶的mRNA表达增加。此外，我们的数据不支持环氧米星对急性恶病质引起的肌肉萎缩的任何预防作用，因为蛋白酶体的活性没有被进一步抑制。
The ubiquitin-proteasome pathway (UPP) is a major protein degradation pathway that is activated during sepsis and has been proposed as a therapeutic target for preventing skeletal muscle loss due to cachexia. Although several studies have investigated the modulation of proteasome activity in response to LPS administration, none have characterized the overall UPP response to LPS administration in the fate of proteasome inhibition. Here, we determined the modulation pattern of the main key components of the UPP in the gastrocnemius (GAS) of mice during the acute phase of lipopolysaccharide (LPS)-mediated endotoxemia (7.5 mg/kg – 8 h) by measuring all three β1, β2 and β5 activites of the 20S and 26S proteasomes, the levels of steady state polyubiquitinated proteins, mRNA levels of muscle ligases, as well as signaling pathways regulating the UPP. Another goal was to assess the effects of administration of a specific proteasome inhibitor (epoxomicin, 0.5 mg/kg) on UPP response to sepsis. The acute phase of LPS-induced endotoxemia lowered GAS/body weight ratio and increased MuRF1 and MAFbx mRNA concomitantly to an activation of the pathways known to regulate their expression. Unexpectedly, we observed a decrease in all 20S and 26S proteasome activities measured in GAS, which might be related to oxidative stress, as oxidized proteins (carbonyl levels) increase with LPS. While significantly inhibiting 20S and 26S proteasome β5 activities in heart and liver, epoxomicin did not lower proteasome activity in GAS. However, the increase in mRNA expression of the muscle ligases MuRF1 and MAFbx were partially rescued without affecting the other investigated signaling pathways. LPS also strongly activated autophagy, which could explain the observed GAS atrophy with LPS-induced reduction of proteasome activity. Our results highlight an opposite regulation of UPP in the early hours of LPS-induced muscle atrophy by showing reduced proteasome activities and increased mRNA expression of muscle specific ligases. Furthermore, our data do not support any preventive effect of epoxomicin in muscle atrophy due to acute cachexia since proteasome activities are not further repressed.
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