Infection and chronic disease activate a systemic brain-muscle signaling axis, 2024, Johnson et al

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

Editor’s summary
Neuroinflammation can cause symptoms outside of the central nervous system (CNS), including muscle pain and fatigue, yet how inflammatory signals in the brain are communicated to muscle remains to be determined. Using multiple models of CNS stress in fruit flies, Yang et al. identified that reactive oxygen species accumulation in the brain promoted expression of Upd3, a Drosophila ortholog of interleukin-6 (IL-6). IL-6 activated JAK-STAT signaling in skeletal muscle, resulting in mitochondrial dysfunction–impaired motor function. This axis was also activated in mice after CNS stress and evident in humans with neuroinflammation. This work identifies a conserved brain-to-muscle signaling axis that regulates muscle performance, which may be a promising therapeutic target. —Hannah Isles

Abstract
Infections and neurodegenerative diseases induce neuroinflammation, but affected individuals often show nonneural symptoms including muscle pain and muscle fatigue. The molecular pathways by which neuroinflammation causes pathologies outside the central nervous system (CNS) are poorly understood.

We developed multiple models to investigate the impact of CNS stressors on motor function and found that Escherichia coli infections and SARS-CoV-2 protein expression caused reactive oxygen species (ROS) to accumulate in the brain. ROS induced expression of the cytokine Unpaired 3 (Upd3) in Drosophila and its ortholog, IL-6, in mice. CNS-derived Upd3/IL-6 activated the JAK-STAT pathway in skeletal muscle, which caused muscle mitochondrial dysfunction and impaired motor function. We observed similar phenotypes after expressing toxic amyloid-β (Aβ42) in the CNS.

Infection and chronic disease therefore activate a systemic brain-muscle signaling axis in which CNS-derived cytokines bypass the connectome and directly regulate muscle physiology, highlighting IL-6 as a therapeutic target to treat disease-associated muscle dysfunction.

https://www.science.org/doi/10.1126/sciimmunol.adm7908

 

* in mice and fruit flies

Interesting that they got the results using covid

 

At least according to the study. But then again I don't even know, maybe this has always been well known in humans as well?

 

Medical Express
Scientists identify possible way to block muscle fatigue in long COVID, other diseases

quotes:

"Our study suggests that when we get sick, messenger proteins from the brain travel through the bloodstream and reduce energy levels in skeletal muscle. This is more than a lack of motivation to move because we don't feel well. These processes reduce energy levels in skeletal muscle, decreasing the capacity to move and function normally."

...

"We're not sure why the brain produces a protein signal that is so damaging to muscle function across so many different disease categories," Johnson said.

"If we want to speculate about possible reasons this process has stayed with us over the course of human evolution, despite the damage it does, it could be a way for the brain to reallocate resources to itself as it fights off disease. We need more research to better understand this process and its consequences throughout the body.

 

NEWS RELEASE 12-JUL-2024
Brain inflammation triggers muscle weakness after infections
In fruit flies and mice, scientists ID possible way to block muscle fatigue in long COVID, other diseases
https://www.eurekalert.org/news-releases/1050851

 

Fun fact:

Apparently fruit flies are good for genetic studies. Drosophila melanogaster has a short life cycle of about two weeks, and females have a lot of offspring—they can lay hundreds of eggs in a few days. Both these features make them a great system for genetic experiments

 

Johnson added, “Flies and mice that had COVID-associated proteins in the brain showed reduced motor function—the flies didn’t climb as well as they should have, and the mice didn’t run as well or as much as control mice.” We saw similar effects on muscle function when the brain was exposed to bacterial-associated proteins and the Alzheimer’s protein amyloid beta. We also see evidence that this effect can become chronic. Even if an infection is cleared quickly, the reduced muscle performance remains many days longer in our experiments.” Reporting on their experiments, the team further stated, “Using genetic rescue experiments and pharmacological treatments, we conclude cytokine signaling from the CNS is sufficient to impair motor function and that IL-6 could be a therapeutic target to treat muscle dysfunction in response to infections and chronic disease. Brain muscle-communication is thus a central regulator of muscle performance.”

LINK

 

IL-6 has been a target for treating chronic disease for thirty years now. It would works wonders in some but if infection is present most cytokine blockers are the kiss of death. TNF blockers were developed to teat infection and they made it much much worse. The main drawback worldwide with their use is deaths from TB. Blocking TNF, IL-1 and IL-6 are all bad for that.

More widely, we have known that cytokines block muscle function at least since about 1985, when they had different names like PIF or mononuclear cell factor.

And I am not very sure where neuroinflammation itself comes in. People with neuroinflammation tend to be paralysed or comatose from the effects on the nervous system itself. I am afraid I get the impression that the authors don't have much idea of what is generally known about disease mechanisms and, as so often these days, are re-inventing what they hope is a wheel but with square sides.

 

This has come up in my feed as an article in Science Alert optimistically titled...

https://www.sciencealert.com/we-may-have-found-a-target-for-treating-the-fatigue-of-long-covid

tell me about it !

 

I have an all encompassing news feed. This popped up today and may be interesting ...

Study reveals how inflammation weakens muscles during illness (msn.com)

editor's summary

Neuroinflammation can cause symptoms outside of the central nervous system (CNS), including muscle pain and fatigue, yet how inflammatory signals in the brain are communicated to muscle remains to be determined. Using multiple models of CNS stress in fruit flies, Yang et al. identified that reactive oxygen species accumulation in the brain promoted expression of Upd3, a Drosophila ortholog of interleukin-6 (IL-6). IL-6 activated JAK-STAT signaling in skeletal muscle, resulting in mitochondrial dysfunction–impaired motor function. This axis was also activated in mice after CNS stress and evident in humans with neuroinflammation. This work identifies a conserved brain-to-muscle signaling axis that regulates muscle performance, which may be a promising therapeutic target

link to paper
Infection and chronic disease activate a systemic brain-muscle signaling axis | Science Immunology