Patients with infectious or chronic diseases often suffer from both neuroinflammation and nonneural symptoms including muscle pain and muscle fatigue. Although muscle symptoms are often associated with the common cold, or more recently with COVID-19, the pathogenic mechanisms by which infections cause muscle dysfunction are unclear.
We show that CNS-derived immune factors (cytokines) bypass the connectome and directly regulate muscle physiology in response to infectious and chronic diseases. The systemic brain-muscle signaling axis is a completely novel pathway by which the CNS controls muscle function, and is thus a new therapeutic target to prevent muscle dysfunction associated with long-term illnesses.
To study the interaction between neural symptoms and muscle symptoms, we developed multiple models to investigate the impact of CNS stressors on motor function, and found infectious and chronic diseases caused reactive oxygen species (ROS) to accumulate in the brain. ROS induced expression of the cytokine Unpaired 3 (Upd3) in insects, and its orthologue IL-6 in mammals, and CNS-derived Upd3/IL-6 activated the JAK/Stat pathway in skeletal muscle. JAK/Stat signaling caused muscle mitochondrial dysfunction, which disrupted motor function. Infection and chronic disease therefore activate a systemic brain-muscle signaling axis in which CNS-derived immune factors bypass the connectome and directly regulate muscle physiology, highlighting IL-6 as a therapeutic target to treat disease-associated muscle dysfunction.
This work is a result of excellent international collaboration. Seven institutions, including Fudan University, Tsinghua University, Shenzhen Bay Laboratory, Harbin Veterinary Research Institute Chinese Academy of Agricultural Sciences, Washington University School of Medicine in St. Louis, National Cancer Institute, and University of Florida College of Medicine, are contributed to this study.
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