Deletion of quinolinate phosphoribosyltransferase gene accelerates frailty phenotypes and neuromuscular decline with aging in a sex-specific pattern,Aging Cell

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Deletion of quinolinate phosphoribosyltransferase gene accelerates frailty phenotypes and neuromuscular decline with aging in a sex-specific pattern
Aging Cell ( IF 8.0 ) Pub Date : 2023-04-20 , DOI: 10.1111/acel.13849
Tae Chung _{1,

2} , Taylor Bopp ₁ , Chris Ward ₃ , Francesca M Notarangelo ₄ , Robert Schwarcz ₄ , Reyhan Westbrook ₅ , Qian-Li Xue ₅ , Jeremy Walston ₅ , Ahmet Hoke ₂

Affiliation

Decline in neuromuscular function with aging is known to be a major determinant of disability and all-cause mortality in late life. Despite the importance of the problem, the neurobiology of age-associated muscle weakness is poorly understood. In a previous report, we performed untargeted metabolomics on frail older adults and discovered prominent alteration in the kynurenine pathway, the major route of dietary tryptophan degradation that produces neurotoxic intermediate metabolites. We also showed that neurotoxic kynurenine pathway metabolites are correlated with increased frailty score. For the present study, we sought to further examine the neurobiology of these neurotoxic intermediates by utilizing a mouse model that has a deletion of the quinolinate phosphoribosyltransferase (QPRT) gene, a rate-limiting step of the kynurenine pathway. QPRT^−/− mice have elevated neurotoxic quinolinic acid level in the nervous system throughout their lifespan. We found that QPRT^−/− mice have accelerated declines in neuromuscular function in an age- and sex-specific manner compared to control strains. In addition, the QPRT^−/− mice show premature signs of frailty and body composition changes that are typical for metabolic syndrome. Our findings suggest that the kynurenine pathway may play an important role in frailty and age-associated muscle weakness.

中文翻译：

喹啉磷酸核糖基转移酶基因的缺失会加速衰老表型和神经肌肉衰退，且具有性别特异性

众所周知，随着年龄的增长，神经肌肉功能下降是晚年残疾和全因死亡率的主要决定因素。尽管这个问题很重要，但与年龄相关的肌肉无力的神经生物学却知之甚少。在之前的一份报告中，我们对体弱的老年人进行了非靶向代谢组学，发现犬尿氨酸途径发生了显着改变，犬尿氨酸途径是膳食色氨酸降解产生神经毒性中间代谢产物的主要途径。我们还表明，神经毒性犬尿氨酸途径代谢物与虚弱评分增加相关。在本研究中，我们试图利用删除了喹啉磷酸核糖转移酶（QPRT）基因（犬尿氨酸途径的限速步骤）的小鼠模型来进一步检查这些神经毒性中间体的神经生物学。QPRT ^-/−小鼠在其一生中神经系统中的神经毒性喹啉酸水平升高。我们发现，与对照品系相比， QPRT ^{-/−小鼠的神经肌肉功能以年龄和性别特异性的方式加速衰退。}此外，QPRT ^-/−小鼠表现出过早的虚弱迹象和代谢综合征典型的身体成分变化。我们的研究结果表明，犬尿氨酸途径可能在虚弱和与年龄相关的肌肉无力中发挥重要作用。

更新日期：2023-04-20

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