Duchenne muscular dystrophy (DMD) is a lethal degenerative muscle wasting disease caused by the loss of the structural protein dystrophin with secondary pathological manifestations including metabolic dysfunction, mood and behavioral disorders. In the mildly affected mdx mouse model of DMD, brief scruff stress causes inactivity, while more severe subordination stress results in lethality. Here, we investigated the kynurenine pathway of tryptophan degradation and the nicotinamide adenine dinucleotide (NAD+) metabolic pathway in mdx mice and their involvement as possible mediators of mdx stress-related pathology. We identified downregulation of the kynurenic acid shunt, a neuroprotective branch of the kynurenine pathway, in mdx skeletal muscle associated with attenuated peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) transcriptional regulatory activity. Restoring the kynurenic acid shunt by skeletal muscle-specific PGC-1α overexpression in mdx mice did not prevent scruff -induced inactivity, nor did abrogating extrahepatic kynurenine pathway activity by genetic deletion of the pathway rate-limiting enzyme, indoleamine oxygenase 1. We further show that reduced NAD+ production in mdx skeletal muscle after subordination stress exposure corresponded with elevated levels of NAD+ catabolites produced by ectoenzyme cluster of differentiation 38 (CD38) that have been implicated in lethal mdx response to pharmacological β-adrenergic receptor agonism. However, genetic CD38 ablation did not prevent mdx scruff-induced inactivity. Our data do not support a direct contribution by the kynurenine pathway or CD38 metabolic dysfunction to the exaggerated stress response of mdx mice.

中文翻译：

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PGC-1α 过表达或 IDO1 或 CD38 消融后，杜氏肌营养不良 mdx 小鼠模型应激敏感性的保留

杜氏肌营养不良症（DMD）是一种由结构蛋白肌营养不良蛋白缺失引起的致死性退行性肌肉萎缩性疾病，伴有代谢功能障碍、情绪和行为障碍等继发病理表现。在 DMD 轻度受影响的 mdx 小鼠模型中，短暂的颈背应激会导致不活动，而更严重的服从应激会导致死亡。在这里，我们研究了 mdx 小鼠中色氨酸降解的犬尿氨酸途径和烟酰胺腺嘌呤二核苷酸 (NAD+) 代谢途径，以及它们作为 mdx 应激相关病理学的可能介质的参与。我们发现，mdx 骨骼肌中犬尿酸分流（犬尿氨酸途径的一个神经保护分支）的下调与过氧化物酶体增殖物激活受体-γ 共激活物 1 α (PGC-1α) 转录调节活性减弱相关。在 mdx 小鼠中通过骨骼肌特异性 PGC-1α 过度表达来恢复犬尿酸分流并不能阻止颈背诱导的不活动，通过基因删除途径限速酶吲哚胺加氧酶 1 来消除肝外犬尿氨酸途径活性也不能。我们进一步表明在服从应激暴露后，mdx 骨骼肌中 NAD+ 的产生减少，这与分化外酶簇 38 (CD38) 产生的 NAD+ 分解代谢物水平升高相对应，这些分解代谢物与药理 β-肾上腺素能受体激动的致命 mdx 反应有关。然而，基因 CD38 消除并不能阻止 mdx scruff 引起的不活动。我们的数据不支持犬尿氨酸途径或 CD38 代谢功能障碍对 mdx 小鼠过度应激反应的直接影响。