Duchenne muscular dystrophy is a severe pediatric neuromuscular disorder caused by the lack of dystrophin. Identification of biomarkers is needed to support and accelerate drug development. Alterations of metabolites levels in muscle and plasma have been reported in pre-clinical and clinical cross-sectional comparisons. We present here a 7-month longitudinal study comparing plasma metabolomic data in wild-type and mdx mice. A mass spectrometry approach was used to study metabolites in up to five time points per mouse at 6, 12, 18, 24 and 30 weeks of age, providing an unprecedented in depth view of disease trajectories. A total of 106 metabolites were studied. We report a signature of 31 metabolites able to discriminate between healthy and disease at various stages of the disease, covering the acute phase of muscle degeneration and regeneration up to the deteriorating phase. We show how metabolites related to energy production and chachexia (e.g. glutamine) are affected in mdx mice plasma over time. We further show how the signature is connected to molecular targets of nutraceuticals and pharmaceutical compounds currently in development as well as to the nitric oxide synthase pathway (e.g. arginine and citrulline). Finally, we evaluate the signature in a second longitudinal study in three independent mouse models carrying 0, 1 or 2 functional copies of the dystrophin paralog utrophin. In conclusion, we report an in-depth metabolomic signature covering previously identified associations and new associations, which enables drug developers to peripherally assess the effect of drugs on the metabolic status of dystrophic mice.

中文翻译：

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血浆的纵向代谢组学分析能够在杜氏肌营养不良症小鼠模型中模拟疾病的进展。

Duchenne肌营养不良症是由肌营养不良蛋白缺乏引起的一种严重的小儿神经肌肉疾病。需要鉴定生物标志物以支持和加速药物开发。临床前和临床横断面比较中已经报道了肌肉和血浆中代谢物水平的变化。我们在这里提供了一个为期7个月的纵向研究，比较了野生型和mdx小鼠的血浆代谢组学数据。质谱方法用于研究每只小鼠在6、12、18、24和30周龄时多达五个时间点的代谢产物，从而提供了前所未有的疾病轨迹深度视图。共研究了106种代谢物。我们报告了31种代谢物的特征，它们能够区分疾病各个阶段的健康状况和疾病状况，涵盖了肌肉变性和再生的急性期，直至恶化期。我们展示了随着时间的流逝，与能量产生和精神病相关的代谢产物（例如谷氨酰胺）如何在mdx小鼠血浆中受到影响。我们进一步显示签名如何与目前正在开发的营养保健品和药物化合物的分子靶标以及一氧化氮合酶途径（例如精氨酸和瓜氨酸）连接。最后，在第二个纵向研究中，我们在带有0、1或2个功能复制的抗肌萎缩蛋白旁系同源蛋白的三个独立小鼠模型中评估了签名。总之，我们报告了一个深入的代谢组学特征，涵盖了先前确定的关联和新的关联，这使药物开发人员能够从外围评估药物对营养不良小鼠代谢状态的影响。