Comparison of the anticatabolic effects of leucine and Ca-β-hydroxy-β-methylbutyrate in experimental models of cancer cachexia
Comparison of the anticatabolic effects of leucine and Ca-β-hydroxy-β-methylbutyrate in experimental models of cancer cachexia
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DOI：
10.1016/j.nut.2013.11.012
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发表时间：
2014-07-01
期刊：
影响因子：
4.4
通讯作者：
Tisdale, Michael J.
中科院分区：
文献类型：
--
作者：
Mirza, Kamran A.;Pereira, Suzette L.;Tisdale, Michael J.
目的：骨骼肌的丧失是癌症恶病质最严重的特征，目前治疗方法很少。本研究的目的是比较l -亮氨酸和亮氨酸代谢物β -羟基- β -甲基丁酸（Ca-HMB）对肌肉蛋白质代谢的体外和体内的抗代谢作用。方法：对携带恶病质诱导小鼠腺癌16的小鼠和暴露于蛋白水解诱导因子、脂多糖和血管紧张素II的小鼠C-2 C-12肌管进行研究。结果：亮氨酸和HMB均能减弱蛋白水解诱导因子、脂多糖和血管紧张素II诱导的小鼠肌管蛋白质降解增加和蛋白质合成减少。然而，HMB比亮氨酸更有效，因为50 μ M时HMB产生的效果与1 mM时亮氨酸基本相同。亮氨酸和HMB都降低了泛素-蛋白酶体途径的活性，这是通过肌肉裂解物中蛋白酶体的功能（凝乳胰蛋白酶样）酶活性以及结构/酶促蛋白酶体亚基（20 S和19 S）和泛素连接酶（MuRF1和MAFbx）的蛋白水平的Western blot测定的。在患有小鼠腺癌16的小鼠体内研究表明，低剂量的Ca-HMB （0.25 g/kg）在4天内减轻体重损失的效果比亮氨酸（1 g/kg）高60%。结论：Ca-HMB治疗癌症恶病质的临床可行性优于大剂量亮氨酸。(C) 2014爱思唯尔公司版权所有。
Objective: Loss of skeletal muscle is the most debilitating feature of cancer cachexia, and there are few treatments available. The aim of this study was to compare the anticatabolic efficacy of L-leucine and the leucine metabolite beta-hydroxy-beta-methylbutyrate (Ca-HMB) on muscle protein metabolism, both in vitro and in vivo.Methods: Studies were conducted in mice bearing the cachexia-inducing murine adenocarcinoma 16 tumor, and in murine C-2 C-12 myotubes exposed to proteolysis-inducing factor, lipopolysaccharide, and angiotensin II.Results: Both leucine and HMB were found to attenuate the increase in protein degradation and the decrease in protein synthesis in murine myotubes induced by proteolysis-inducing factor, lipopolysaccharide, and angiotensin II. However, HMB was more potent than leucine, because HMB at 50 mu M produced essentially the same effect as leucine at 1 mM. Both leucine and HMB reduced the activity of the ubiquitin-proteasome pathway as measured by the functional (chymotrypsin-like) enzyme activity of the proteasome in muscle lysates, as well as Western blot quantitation of protein levels of the structural/enzymatic proteasome subunits (20 S and 19 S) and the ubiquitin ligases (MuRF1 and MAFbx). In vivo studies in mice bearing the murine adenocarcinoma 16 tumor showed a low dose of Ca-HMB (0.25 g/kg) to be 60% more effective than leucine (1 g/kg) in attenuating loss of body weight over a 4-d period.Conclusion: These results favor the clinical feasibility of using Ca-HMB over high doses of leucine for the treatment of cancer cachexia. (C) 2014 Elsevier Inc. All rights reserved.