Methylarginine metabolites are associated with attenuated muscle protein synthesis in cancer-associated muscle wasting
Methylarginine metabolites are associated with attenuated muscle protein synthesis in cancer-associated muscle wasting
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DOI：
10.1074/jbc.ra120.014884
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发表时间：
2020-12-18
影响因子：
4.8
通讯作者：
Lanza, Ian R.
中科院分区：
文献类型：
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作者：
Kunz, Hawley E.;Dorschner, Jessica M.;Lanza, Ian R.
癌症恶病质的特征在于外周瘦肌肉质量的减少。先前的研究主要集中在增加蛋白质分解作为癌症相关肌肉萎缩的驱动因素。然而，针对分解代谢途径的治疗干预在很大程度上未能保持恶病质中的肌肉质量，这表明可能涉及其他机制。为了寻找新的途径，我们使用非靶向代谢组学来寻找可能与肌肉萎缩有关的代谢物特征。我们给7周龄的C57/BL 6小鼠注射LLC 1肿瘤细胞或载体。21天后，荷瘤小鼠表现出减少的身体和肌肉质量和受损的握力与对照组相比，这是伴随着较低的合成率的混合肌肉蛋白质和肌原纤维和肌浆肌组分。在荷瘤小鼠中，蛋白质合成的减少伴随着线粒体的增大和偶联效率的降低。为了对受损的蛋白质合成产生机制性的见解，我们对血浆和肌肉进行了非靶向代谢组学分析，发现与对照小鼠相比，荷瘤小鼠中两种甲基精氨酸（不对称二甲基精氨酸（ADMA）和N-G-单甲基-L-精氨酸）的浓度增加。与健康对照组相比，人类癌症患者的骨骼肌中ADMA水平也较高。用ADMA处理C2 C12肌管损害蛋白质合成并降低线粒体蛋白质质量。这些结果表明，ADMA水平增加和线粒体变化可能导致癌症恶病质中肌肉蛋白质合成受损，并可能指向减轻癌症恶病质的新治疗靶点。
Cancer cachexia is characterized by reductions in peripheral lean muscle mass. Prior studies have primarily focused on increased protein breakdown as the driver of cancer-associated muscle wasting. Therapeutic interventions targeting catabolic pathways have, however, largely failed to preserve muscle mass in cachexia, suggesting that other mechanisms might be involved. In pursuit of novel pathways, we used untargeted metabolomics to search for metabolite signatures that may be linked with muscle atrophy. We injected 7-week-old C57/BL6 mice with LLC1 tumor cells or vehicle. After 21 days, tumor-bearing mice exhibited reduced body and muscle mass and impaired grip strength compared with controls, which was accompanied by lower synthesis rates of mixed muscle protein and the myofibrillar and sarcoplasmic muscle fractions. Reductions in protein synthesis were accompanied by mitochondrial enlargement and reduced coupling efficiency in tumor-bearing mice. To generate mechanistic insights into impaired protein synthesis, we performed untargeted metabolomic analyses of plasma and muscle and found increased concentrations of two methylarginines, asymmetric dimethylarginine (ADMA) and N-G-monomethyl-l-arginine, in tumor-bearing mice compared with control mice. Compared with healthy controls, human cancer patients were also found to have higher levels of ADMA in the skeletal muscle. Treatment of C2C12 myotubes with ADMA impaired protein synthesis and reduced mitochondrial protein quality. These results suggest that increased levels of ADMA and mitochondrial changes may contribute to impaired muscle protein synthesis in cancer cachexia and could point to novel therapeutic targets by which to mitigate cancer cachexia.