Infections and neurodegenerative diseases induce neuroinflammation, but affected individuals often show nonneural symptoms including muscle pain and muscle fatigue. The molecular pathways by which neuroinflammation causes pathologies outside the central nervous system (CNS) are poorly understood. We developed multiple models to investigate the impact of CNS stressors on motor function and found that Escherichia coli infections and SARS-CoV-2 protein expression caused reactive oxygen species (ROS) to accumulate in the brain. ROS induced expression of the cytokine Unpaired 3 (Upd3) in Drosophila and its ortholog, IL-6, in mice. CNS-derived Upd3/IL-6 activated the JAK-STAT pathway in skeletal muscle, which caused muscle mitochondrial dysfunction and impaired motor function. We observed similar phenotypes after expressing toxic amyloid-β (Aβ42) in the CNS. Infection and chronic disease therefore activate a systemic brain-muscle signaling axis in which CNS-derived cytokines bypass the connectome and directly regulate muscle physiology, highlighting IL-6 as a therapeutic target to treat disease-associated muscle dysfunction.

中文翻译：

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感染和慢性疾病激活全身脑肌肉信号轴


感染和神经退行性疾病会引起神经炎症，但受影响的个体通常会表现出非神经症状，包括肌肉疼痛和肌肉疲劳。神经炎症引起中枢神经系统（CNS）以外病变的分子途径尚不清楚。我们开发了多种模型来研究中枢神经系统应激源对运动功能的影响，发现大肠杆菌感染和 SARS-CoV-2 蛋白表达导致活性氧 (ROS) 在大脑中积聚。 ROS 诱导果蝇中细胞因子 Unpaired 3 (Upd3) 及其直系同源物 IL-6 在小鼠中的表达。 CNS 衍生的 Upd3/IL-6 激活骨骼肌中的 JAK-STAT 通路，导致肌肉线粒体功能障碍和运动功能受损。在中枢神经系统中表达有毒的淀粉样蛋白-β (Aβ42) 后，我们观察到了类似的表型。因此，感染和慢性疾病会激活系统性脑肌肉信号轴，其中中枢神经系统衍生的细胞因子绕过连接组并直接调节肌肉生理学，这凸显了 IL-6 作为治疗疾病相关肌肉功能障碍的治疗靶点。