Infection and chronic disease activate a brain-muscle signaling axis that regulates muscle performance

  1. Shuo Yang
  2. Meijie Tian
  3. Yulong Dai
  4. Shengyong Feng
  5. Yunyun Wang
  6. Deepak Chhangani
  7. Tiffany Ou
  8. Wenle Li
  9. Ze Yang
  10. Jennifer McAdow
  11. Diego E. Rincon-Limas
  12. Xin Yin
  13. Wanbo Tai
  14. Gong Cheng
  15. Aaron Johnson
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Abstract

Graphic abstract

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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.

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