Astrocytes-derived LCN2 triggers EV-A71–induced muscle soreness via accumulating lactate

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-05-16 DOI:10.1126/sciadv.adt9837

Qiao You, Jing Wu, Chaoyong Wang, Deyan Chen, Shiji Deng, Yurong Cai, Nan Zhou, Ruining Lyu, Yajie Qian, Yi Xie, Miao He, Zhiwei Wu

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Abstract

Viral muscle soreness (VMS) is a common feature during acute viral infections, including those caused by enteroviruses, and it substantially diminishes patients’ quality of life. At present, we aim to establish the “brain-muscle” axis to explore the underlying mechanisms of VMS. We initially observed that diminished pain threshold occurred in enterovirus A71 (EV-A71)–infected C57BL/6J and AG6 mice. Subsequently, RNA sequencing data showed that lipocalin 2 (LCN2) was up-regulated during multiple viral infections, including EV-A71, Japanese encephalitis virus, vesicular stomatitis virus, and West Nile virus, which all caused VMS. As expected, Lcn2-deficient C57BL/6 J (Lcn2^−/−) mice exhibited greater pain tolerance, as shown by stronger grip force and stable motor function after EV-A71 infection. Mechanistically, EV-A71–induced high-mobility group 1 (HMGB1) stimulated astrocyte-derived LCN2 secreted into the circulatory system, which enhanced glycolysis and induced lactate buildup in muscle through increasing pyruvate dehydrogenase kinase 1 (PDK1) expression and decreasing pyruvate dehydrogenase (PDH) activity. Together, HMGB1/LCN2/PDK1/lactate pathway in the brain-muscle axis promoted VMS development.

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星形胶质细胞衍生的LCN2通过积累乳酸触发ev - a71诱导的肌肉酸痛

病毒性肌肉酸痛（VMS）是急性病毒感染（包括由肠道病毒引起的感染）期间的常见特征，它大大降低了患者的生活质量。目前，我们的目标是建立“脑肌”轴，探讨VMS的潜在机制。我们最初观察到感染肠病毒A71 （EV-A71）的C57BL/6J和AG6小鼠疼痛阈值降低。随后，RNA测序数据显示，脂质体蛋白2 （lipocalin 2, LCN2）在多种病毒感染中表达上调，包括EV-A71病毒、日本脑炎病毒、水疱性口炎病毒和西尼罗病毒，这些病毒都引起VMS。正如预期的那样，Lcn2缺陷的C57BL/6 J （Lcn2−/−）小鼠在感染EV-A71后表现出更强的握力和稳定的运动功能，表现出更强的疼痛耐受性。机制上，ev - a71诱导的高迁移率组1 （HMGB1）刺激星形胶质细胞衍生的LCN2分泌到循环系统，通过增加丙酮酸脱氢酶激酶1 （PDK1）的表达和降低丙酮酸脱氢酶（PDH）的活性来促进糖酵解和诱导肌肉中乳酸的积累。脑肌轴HMGB1/LCN2/PDK1/乳酸通路共同促进VMS的发育。

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.