Abstract
Graphic abstract
Summary Infections and neurodegenerative diseases induce neuroinflammation, but affected individuals often show a number of non-neural symptoms including muscle pain and muscle fatigue. The molecular pathways by which neuroinflammation causes pathologies outside the central nervous system (CNS) are poorly understood, so we developed three models to investigate the impact of neuroinflammation on muscle performance. We found that bacterial infection, COVID-like viral infection, and expression of a neurotoxic protein associated with Alzheimer′ s disease promoted the accumulation of reactive oxygen species (ROS) in the brain. Excessive ROS induces the expression of the cytokine Unpaired 3 (Upd3) in insects, or its orthologue IL-6 in mammals, and CNS-derived Upd3/IL-6 activates the JAK/Stat pathway in skeletal muscle. In response to JAK/Stat signaling, mitochondrial function is impaired and muscle performance is reduced. Our work uncovers a brain-muscle signaling axis in which infections and chronic diseases induce cytokine-dependent changes in muscle performance, suggesting IL-6 could be a therapeutic target to treat muscle weakness caused by neuroinflammation.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵10 Lead corresponding author
↵* These authors contribute equally to this manuscript
In the revised manuscript, we identify an inter-organ communication pathway that is activated by neuroinflammation. The signaling ligand Upd3/IL-6 is expressed in the brain in response to neuroinflammation, and activates the JAK/Stat signaling pathway in skeletal muscle. Once active, the JAK/Stat pathway inhibits mitochondrial function and reduces skeletal muscle performance. Neuroinflammation therefore activates a systemic signaling response that alters muscle performance.
