You Qiao, Wu Jing, Wang Chaoyong, Chen Deyan, Deng Shiji, Cai Yurong, Zhou Nan, Lyu Ruining, Qian Yajie, Xie Yi, He Miao, Wu Zhiwei
Center for Public Health Research, Medical School of Nanjing University, Nanjing, China.
Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, China.
Sci Adv. 2025 May 16;11(20):eadt9837. doi: 10.1126/sciadv.adt9837.
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, -deficient C57BL/6 J () 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.
病毒性肌肉酸痛（VMS）是急性病毒感染期间的常见症状，包括由肠道病毒引起的感染，它会显著降低患者的生活质量。目前，我们旨在建立“脑-肌肉”轴，以探索VMS的潜在机制。我们最初观察到，在感染肠道病毒A71（EV-A71）的C57BL/6J和AG6小鼠中出现痛阈降低。随后，RNA测序数据显示，在包括EV-A71、日本脑炎病毒、水疱性口炎病毒和西尼罗河病毒在内的多种病毒感染期间，脂质运载蛋白2（LCN2）上调，这些病毒都会导致VMS。正如预期的那样，LCN2基因缺陷的C57BL/6J（Lcn2-/-）小鼠表现出更强的疼痛耐受性，如在感染EV-A71后握力更强和运动功能稳定所示。从机制上讲，EV-A71诱导的高迁移率族蛋白1（HMGB1）刺激星形胶质细胞衍生的LCN2分泌到循环系统中，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，增强糖酵解并诱导肌肉中乳酸积累。总之，脑-肌肉轴中的HMGB1/LCN2/PDK1/乳酸途径促进了VMS的发展。
