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

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, <i>Lcn2</i>-deficient C57BL/6 J (<i>Lcn2</i>^-/-) 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.