Kynurenine, a Tryptophan Metabolite That Increases with Age, Induces Muscle Atrophy and Lipid Peroxidation
Kynurenine, a Tryptophan Metabolite That Increases with Age, Induces Muscle Atrophy and Lipid Peroxidation
复制标题
DOI：
10.1155/2019/9894238
复制
发表时间：
2019-10-13
影响因子：
--
通讯作者：
Hamrick, Mark W.
中科院分区：
文献类型：
--
作者：
Kaiser, Helen;Yu, Kanglun;Hamrick, Mark W.
随着年龄的增长，肌肉质量损失（肌肉减少症）的细胞和分子机制还没有得到很好的理解;然而，异时共生实验表明，循环因素可能发挥作用。犬尿氨酸（KYN）是一种循环色氨酸代谢物，已知其随年龄增长而增加，并且是芳烃受体（Ahr）的配体。在这里，我们测试了这样一个假设，即KYN激活Ahr在随着年龄增长的肌肉损失中起作用。结果表明，小鼠和人成肌细胞的KYN治疗增加了活性氧（ROS）的水平2倍，KYN治疗在体内减少肌肉的大小和力量，并增加肌肉脂质过氧化作用的年轻小鼠。PCR阵列数据表明，KYN处理的肌纤维尺寸减小减少了蛋白质合成标记物，而泛素连接酶基因表达没有显著增加。KYN是由吲哚胺2，3-双加氧酶（IDO）产生的，用IDO抑制剂1-甲基-D-色氨酸治疗的老年小鼠显示肌纤维尺寸和肌肉力量增加。体外Ahr的小分子抑制和体内Ahr敲除并不能阻止KYN诱导的ROS增加，这表明KYN可以直接增加ROS，而不依赖于Ahr的激活。蛋白质分析确定极长链酰基辅酶A脱氢酶作为KYN激活的因子，可能会增加ROS和脂质过氧化。我们的数据表明，IDO抑制可能代表了一种新的治疗方法，用于预防肌肉减少症和可能与KYN积累相关的其他年龄相关的疾病，如骨丢失和神经变性。
The cellular and molecular mechanisms underlying loss of muscle mass with age (sarcopenia) are not well-understood; however, heterochronic parabiosis experiments show that circulating factors are likely to play a role. Kynurenine (KYN) is a circulating tryptophan metabolite that is known to increase with age and is a ligand of the aryl hydrocarbon receptor (Ahr). Here, we tested the hypothesis that KYN activation of Ahr plays a role in muscle loss with aging. Results indicate that KYN treatment of mouse and human myoblasts increased levels of reactive oxygen species (ROS) 2-fold and KYN treatment in vivo reduced muscle size and strength and increased muscle lipid peroxidation in young mice. PCR array data indicate that muscle fiber size reduction with KYN treatment reduces protein synthesis markers whereas ubiquitin ligase gene expression is not significantly increased. KYN is generated by the enzyme indoleamine 2,3-dioxygenase (IDO), and aged mice treated with the IDO inhibitor 1-methyl-D-tryptophan showed an increase in muscle fiber size and muscle strength. Small-molecule inhibition of Ahr in vitro, and Ahr knockout in vivo, did not prevent KYN-induced increases in ROS, suggesting that KYN can directly increase ROS independent of Ahr activation. Protein analysis identified very long-chain acyl-CoA dehydrogenase as a factor activated by KYN that may increase ROS and lipid peroxidation. Our data suggest that IDO inhibition may represent a novel therapeutic approach for the prevention of sarcopenia and possibly other age-associated conditions associated with KYN accumulation such as bone loss and neurodegeneration.