Introduction
This study investigates how brain infections and neurodegenerative diseases not only impact the brain, but also lead to muscle problems such as pain and fatigue. Researchers focused on how infections, such as those from E. coli bacteria or SARS-CoV-2 proteins affect brain function and, consequently, muscle performance. They discovered that these infections increase the production of reactive oxygen species (ROS) in the brain, which triggers the release of a molecule called Upd3 (or IL-6 in mice). This molecule travels from the brain to the muscles, causing dysfunction in muscle cells and impairing muscle function.
Summary of Key Findings
- Impact of CNS Infections:
- Infections in the central nervous system (CNS) with E. coli or SARS-CoV-2 proteins significantly reduce muscle mitochondrial activity, and impair motor function in model organisms. This effect is specific to CNS infections and does not occur when muscles are directly infected.
- Role of Upd3 Cytokine:
- Upd3, a cytokine produced in the CNS, plays a crucial role in these effects. When Upd3 is expressed in neurons, it leads to reduced motor abilities and muscle dysfunction. Lowering Upd3 levels in infected organisms helps reverse these impairments, highlighting its central role.
- Mechanistic Insights:
- The study reveals that Upd3 activates a signalling pathway called JAK-STAT in skeletal muscle, disrupting mitochondrial function. This pathway is triggered by ROS produced during infections. Reducing ROS or inhibiting JAK-STAT signalling improves muscle function in infected model organisms.
- Independence from IMD Pathway:
- The IMD immune pathway affects motor function but does not cause the mitochondrial dysfunction seen with Upd3 activation. This indicates that the Upd3-mediated brain-to-muscle signaling operates independently of the IMD pathway.
- Viral Stress Model:
- SARS-CoV-2 protein ORF3a also induces Upd3 signalling, and affects muscle function even after the initial infection has cleared. This suggests that chronic cytokine signalling could contribute to long-term issues like those observed in Long Covid.
Conclusion
The study highlights the importance of cytokine signaling, particularly through Upd3/IL-6, in regulating muscle function during brain infections. It suggests that infections and stressors increase ROS in the brain, activating a signaling pathway that disrupts muscle function. This pathway operates independently of the neural connectome, and may be a potential therapeutic target. The findings also suggest that cytokines like Upd3 might cross the blood-brain barrier, and affect systemic muscle function. The implications extend to various conditions, including cancer, meningitis, and Long Covid, where chronic cytokine signaling might play a role. Targeting IL-6 and related pathways could offer new treatments for muscle dysfunction associated with CNS infections, and chronic diseases.
Yang, Shuo, et al. “Infection and Chronic Disease Activate a Systemic Brain-Muscle Signaling Axis.” Science Immunology, vol. 9, no. 97, 2024, pp. eadm7908-, https://doi.org/10.1126/sciimmunol.adm7908.