Department of Kinesiology, Faculty of Applied Health Sciences, Brock University, St Catharines, Ontario, Canada.
Centre for Bone and Muscle Health, Brock University, St Catharines, Ontario, Canada.
Exp Physiol. 2022 Sep;107(9):1029-1036. doi: 10.1113/EP090381. Epub 2022 Aug 15.
What is the central question in this study? Promoting muscle health with regular aerobic exercise can improve mental health through a kynurenine metabolic pathway: do conditions of muscle disease such as muscular dystrophy negatively influence this pathway? What is the main finding and its importance? The DBA/2J mdx model of Duchenne muscular dystrophy exhibits altered kynurenine metabolism with less kynurenic acid and peroxisome proliferator-activated receptor-γ coactivator 1-α and higher levels of tumour necrosis factor α mRNA - results associated with anxiety-like behaviour.
Regular exercise can direct muscle kynurenine (KYN) metabolism toward the neuroprotective branch of the kynurenine pathway thereby limiting the accumulation of neurotoxic metabolites in the brain and contributing to mental resilience. However, the effect of muscle disease on KYN metabolism has not yet been investigated. Previous work has highlighted anxiety-like behaviours in approximately 25% of patients with Duchenne muscular dystrophy (DMD), possibly due to altered KYN metabolism. Here, we characterized KYN metabolism in mdx mouse models of DMD. Young (8-10 week old) DBA/2J (D2) mdx mice, but not age-matched C57BL/10 (C57) mdx mice, had lower levels of circulating kynurenic acid (KYNA) and lower KYNA:KYN ratio compared with their respective wild-type (WT) controls. While both C57 and D2 mdx mice displayed signs of anxiety-like behaviour, spending more time in the corners of the arena during a novel object recognition test, this effect was more prominent in D2 mdx mice. Correlational analysis detected a significant negative association between KYNA:KYN levels and time spent in corners in D2 mice, but not C57 mice. In extensor digitorum longus muscles from D2 mdx mice, but not C57 mdx mice, we found lowered protein levels of peroxisome proliferator-activated receptor-γ coactivator 1-α and kynurenine amino transferase-1 enzyme when compared with WT. Furthermore, D2 mdx quadriceps muscles had the highest level of tumour necrosis factor α expression, which is suggestive of enhanced inflammation. Thus, our pilot work shows that KYN metabolism is altered in D2 mdx mice, with a potential contribution from altered muscle health.
本研究的核心问题是什么？通过规律的有氧运动促进肌肉健康可以通过犬尿氨酸代谢途径改善心理健康：肌肉疾病（如肌营养不良症）的状况是否会对该途径产生负面影响？主要发现及其重要性是什么？DBA/2J mdx 模型的杜氏肌营养不良症表现出犬尿氨酸（KYN）代谢的改变，犬尿氨酸酸和过氧化物酶体增殖物激活受体-γ共激活物 1-α水平较低，肿瘤坏死因子 α mRNA 水平较高 - 与焦虑样行为相关的结果。
有规律的运动可以使肌肉犬尿氨酸（KYN）代谢向犬尿氨酸途径的神经保护分支方向发展，从而限制了大脑中神经毒性代谢物的积累，并有助于心理适应力。然而，肌肉疾病对 KYN 代谢的影响尚未得到研究。以前的工作强调了大约 25%的杜氏肌营养不良症（DMD）患者的焦虑样行为，可能是由于 KYN 代谢的改变。在这里，我们描述了 DMD 的 mdx 小鼠模型中的 KYN 代谢。年轻（8-10 周龄）的 DBA/2J（D2）mdx 小鼠，但不是年龄匹配的 C57BL/10（C57）mdx 小鼠，与各自的野生型（WT）对照相比，循环犬尿氨酸酸（KYNA）水平较低，KYNA：KYN 比值较低。虽然 C57 和 D2 mdx 小鼠都表现出焦虑样行为的迹象，在新物体识别测试中更多时间停留在竞技场的角落，但这种影响在 D2 mdx 小鼠中更为明显。相关性分析检测到 D2 小鼠中 KYNA：KYN 水平与停留在角落的时间之间存在显著负相关，但 C57 小鼠则没有。在 D2 mdx 小鼠的伸趾长肌中，但不是 C57 mdx 小鼠，与 WT 相比，过氧化物酶体增殖物激活受体-γ共激活物 1-α和犬尿氨酸氨基转移酶-1 酶的蛋白水平降低。此外，D2 mdx 股四头肌的肿瘤坏死因子 α 表达水平最高，提示炎症增强。因此，我们的初步工作表明，D2 mdx 小鼠的 KYN 代谢发生改变，这可能与肌肉健康状况的改变有关。
