Mechanism of the attenuation of proteolysis-inducing factor stimulated protein degradation in muscle by β-hydroxy-β-methylbutyrate
Mechanism of the attenuation of proteolysis-inducing factor stimulated protein degradation in muscle by β-hydroxy-β-methylbutyrate
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DOI：
10.1158/0008-5472.can-04-1760
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发表时间：
2004-12-01
期刊：
影响因子：
11.2
通讯作者：
Tisdale, MJ
中科院分区：
文献类型：
--
作者：
Smith, HJ;Wyke, SM;Tisdale, MJ
亮氨酸代谢物 β-羟基-β-甲基丁酸 (HMB) 通过减弱泛素-蛋白酶体蛋白水解途径，防止癌症引起的体重减轻中的肌肉蛋白降解。为了研究这种作用的机制，使用鼠肌管作为骨骼肌的替代模型，在体外研究了 HMB 对蛋白质分解和细胞内信号传导的作用，从而导致肿瘤因子蛋白水解诱导因子 (PIF) 增加蛋白酶体表达。对 HMB 和二十碳五烯酸 (EPA)（一种已知的 PIF 信号传导抑制剂）的作用进行了比较。在浓度为 50 μmol/L 时，EPA 和 HMB 完全减弱 PIF 诱导的蛋白质降解和泛素蛋白酶体蛋白水解途径的诱导（由“胰凝乳蛋白酶样”酶活性以及 20S 蛋白酶体 α 和 β 亚基以及 19S 调节子的 p42 亚基的蛋白质表达确定）。 PIF 诱导的蛋白质降解的主要事件被认为是从膜磷脂中释放花生四烯酸，并且这一过程被 EPA 而不是 HMB 减弱，这表明 HMB 可能在 PIF 信号传导途径的另一个步骤中发挥作用。浓度为 50 μmol/L 的 EPA 和 HMB 减弱了 PIF 诱导的蛋白激酶 C 的激活以及随后抑制剂 kappaBalpha 的降解和核因子 kappaB 的核积累。 EPA 和 HMB 还减弱 PIF 对 p42/44 丝裂原激活蛋白激酶的磷酸化，这被认为在 PIF 诱导的蛋白酶体表达中很重要。这些结果表明，HMB 减弱了 PIF 诱导的激活并增加了泛素蛋白酶体蛋白水解途径的基因表达，从而减少了蛋白质降解。
The leucine metabolite beta-hydroxy-beta-methylbutyrate (HMB) prevents muscle protein degradation in cancer-induced weight loss through attenuation of the ubiquitin-proteasome proteolytic pathway. To investigate the mechanism of this effect, the action of HMB on protein breakdown and intracellular signaling leading to increased proteasome expression by the tumor factor proteolysis-inducing factor (PIF) has been studied ill vitro using murine myotubes as a surrogate model of skeletal muscle. A comparison has been made of the effects of HMB and those of eicosapentaenoic acid (EPA), a known inhibitor of PIF signaling. At a concentration of 50 mumol/L, EPA and HMB completely attenuated PIF-induced protein degradation and induction of the ubiquitin-proteasome proteolytic pathway, as determined by the "chymotrypsin-like" enzyme activity, as well as protein expression of 20S proteasome alpha- and beta-subunits and subunit p42 of the 19S regulator. The primary event in PIF-induced protein degradation is thought to be release of arachidonic acid from membrane phospholipids, and this process was attenuated by EPA, but not HMB, suggesting that HMB might act at another step in the PIF signaling pathway. EPA and HMB at a concentration of 50 mumol/L attenuated PIF-induced activation of protein kinase C and the subsequent degradation of inhibitor kappaBalpha and nuclear accumulation of nuclear factor kappaB. EPA and HMB also attenuated phosphorylation of p42/44 mitogen-activated protein kinase by PIF, thought to be important in PIF-induced proteasome expression. These results suggest that HMB attenuates PIF-induced activation and increased gene expression of the ubiquitin-proteasome proteolytic pathway, reducing protein degradation.