Sarcopenia in a mice model of chronic liver disease: role of the ubiquitin-proteasome system and oxidative stress
Sarcopenia in a mice model of chronic liver disease: role of the ubiquitin-proteasome system and oxidative stress
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DOI：
10.1007/s00424-018-2167-3
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发表时间：
2018-10-01
影响因子：
4.5
通讯作者：
Cabello-Verrugio, Claudio
中科院分区：
文献类型：
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作者：
Campos, Fabian;Abrigo, Johanna;Cabello-Verrugio, Claudio
骨质疏松症是由于年龄增长或继发于慢性疾病(如慢性肝病)而导致的肌肉质量和力量的丧失。虽然不是所有类型的肌纤维减少症都有相同的特征，但最常见的是纤维直径和肌球蛋白重链(MHC)水平降低，泛素-蛋白酶体系统(UPS)和活性氧(ROS)活性增加。本研究旨在探讨肝毒素5-二乙氧甲酰基-1，4-二氢氯仿(DDC)引起的慢性肝病继发的骨质疏松症。为此，选用4月龄雄性C57BL6小鼠，分别饲喂普通饲料和添加DDC的饲料6周。对活着的小鼠进行了功能测试，以评估肌肉力量、活动度和运动技能。通过电生理方法测定离体腓肠肌的肌力。还测定了腓肠肌组织中肌球蛋白重链(MHC)、E3泛素连接酶、ROS和氧化修饰蛋白的纤维直径、总蛋白和泛素化蛋白水平。我们的结果表明，喂食DDC饮食的小鼠出现肌肉萎缩，表现为肌肉质量的丧失和肌肉力量的下降。喂食DDC饲料的小鼠肌肉纤维直径和MHC水平降低，Murf-1和阿托金-1蛋白水平增加，ROS水平和氧化修饰蛋白水平增加。此外，对照组和DDC小鼠具有相同的食物和水摄入量以及活动能力。我们的结果表明，患有CLD的小鼠出现了肌原纤维蛋白水平降低、UPS增加和氧化应激的骨骼减少，但没有表现为卡路里摄取受损或运动不动。
Sarcopenia is the loss of muscle mass and strength produced by aging or secondary to chronic diseases such as chronic liver disease (CLD). Although not all types of sarcopenia involve the same features, the most common are decreased fiber diameter and myosin heavy chain (MHC) levels, increased activity of ubiquitin-proteasome system (UPS) and reactive oxygen species (ROS). In this study, we aim to characterize the development of sarcopenia secondary to CLD induced by the hepatotoxin 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). For this purpose, four-months-old male C57BL6 mice were fed with normal diet or DDC supplemented diet for 6weeks. Functional tests to evaluate muscle strength, mobility, and motor skills were performed in alive mice. The muscle strength in isolated gastrocnemius was also assayed via electrophysiological measurements. Morphometric measures of fibers' diameter, total and ubiquitinated protein levels of myosin heavy chain (MHC), E3 ubiquitin ligases, ROS, and oxidation-dependent modified proteins in gastrocnemius tissue were also determined. Our results demonstrated that mice fed the DDC diet developed muscle wasting as evidenced by a loss of muscle mass and decreased muscle strength. The muscles of mice fed with DDC diet have a decreased diameter of fibers and MHC levels, also as increased MuRF-1 and atrogin-1 protein levels, ROS levels, and oxidation-modified protein levels. Additionally, control and DDC mice have the same food and water intake as well as mobility. Our results demonstrate mice with CLD develop sarcopenia involving decreased levels of myofibrillar proteins, increased UPS, and oxidative stress, but not for impaired caloric intake or immobility.