Infection and chronic disease activate a systemic brain-muscle signaling axis.

Area of Science:

• Neuroimmunology
• Molecular Biology
• Muscle Physiology

Background:

• Neuroinflammation, triggered by infections and neurodegenerative diseases, is linked to non-neural symptoms like muscle pain and fatigue.
• The mechanisms by which central nervous system (CNS) inflammation impacts peripheral tissues, particularly muscle, remain unclear.

Purpose of the Study:

• To investigate the molecular pathways connecting CNS stressors to systemic pathologies, specifically muscle dysfunction.
• To identify potential therapeutic targets for mitigating disease-associated muscle weakness.

Main Methods:

• Developed Drosophila and mouse models simulating infections (Escherichia coli) and neurodegenerative conditions (amyloid-β expression).
• Measured reactive oxygen species (ROS) in the brain, cytokine expression (Upd3/IL-6), and JAK-STAT pathway activation in skeletal muscle.
• Assessed motor function and muscle mitochondrial health.

Main Results:

• CNS stressors (infections, SARS-CoV-2 protein, Aβ42) induced brain ROS accumulation.
• Brain ROS upregulated Upd3/IL-6, which activated the JAK-STAT pathway in skeletal muscle.
• This systemic signaling axis resulted in muscle mitochondrial dysfunction and impaired motor function.

Conclusions:

• A novel brain-muscle signaling axis exists, where CNS-derived cytokines mediate systemic effects during infection and chronic disease.
• Interleukin-6 (IL-6) is identified as a key mediator in this axis and a potential therapeutic target for muscle dysfunction.
• Understanding this pathway offers insights into non-neural symptoms associated with neurological conditions.