Infections and neurodegenerative diseases trigger inflammation in the brain. However, for reasons that are not yet clear, patients with brain inflammation often develop muscle problems that do not appear to be directly related to the central nervous system. In an effort to understand this connection, researchers at Washington University School of Medicine in St. Louis have discovered that brain inflammation triggers the release of a specific protein that travels from the brain to the muscles, causing a loss of muscle function.
Using experimental models with flies and mice, the study also identified methods to block this process, opening the possibility of developing treatments or preventive measures for muscle atrophy related to inflammatory diseases. These conditions include bacterial infections, Alzheimer’s disease and long COVID. The findings of this research were published on July 12 in the journal Science Immunology.
“We’re interested in understanding the very profound muscle fatigue that’s associated with some common diseases,” said senior author Aaron Johnson, associate professor of developmental biology. “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 just a lack of motivation to move because we don’t feel well. These processes reduce energy levels in skeletal muscle, decreasing the ability to move and function normally.”
“Our study suggests that when we get sick, messenger proteins from the brain travel through the bloodstream and reduce energy levels in skeletal muscle.”
To study the effects of brain inflammation on muscle function, the researchers modeled three different types of diseases: a bacterial infection by E. coli, a viral infection by SARS-CoV-2, and Alzheimer’s disease.
During brain inflammation, inflammatory proteins characteristic of these diseases induce the buildup of harmful chemicals known as reactive oxygen species. These reactive oxygen species trigger brain cells to produce an immune system molecule called interleukin-6 (IL-6), which is dispersed throughout the body via the bloodstream.
The study found that IL-6 in mice and the equivalent protein in fruit flies reduce energy production in muscle mitochondria, which are the energy factories of cells. “Flies and mice that had COVID-associated proteins in their brains showed reduced motor function; the flies did not climb as well as they should have, and the mice did not run as well or as long as control mice,” Johnson explained.
“We saw similar effects on muscle function when the brain was exposed to bacteria-associated proteins and Alzheimer’s amyloid beta protein. We also see evidence that this effect can become chronic. Even if an infection clears quickly, the reduction in muscle performance persists for many more days in our experiments.”
Johnson, along with collaborators at the University of Florida and first author Shuo Yang, who conducted this research as a postdoc in Johnson’s lab, argue that these processes are likely relevant in humans.
Targets to combat muscle weakness in inflammatory diseases
Meningitis, a bacterial infection of the brain, is known to increase IL-6 levels and may be associated with impaired muscle development. For example, in COVID-19 patients, SARS-CoV-2 inflammatory proteins have been found in the brain during autopsies, and numerous long-haul COVID patients report extreme fatigue and muscle weakness long after the initial infection has subsided.
Similarly, patients with Alzheimer’s disease also show elevated levels of IL-6 in the blood and experience muscle weakness.
The study highlights potential targets for preventing or treating muscle weakness linked to brain inflammation. The researchers found that IL-6 activates the JAK-STAT pathway in muscles, leading to a decrease in mitochondrial energy production.
The study identifies potential targets for preventing or treating muscle weakness related to brain inflammation. The researchers found that IL-6 activates what is called the JAK-STAT pathway in muscle, and this is what causes the reduction in mitochondrial energy production.
Several therapies already approved by the Food and Drug Administration (FDA) for other diseases can block this pathway. JAK inhibitors, as well as several monoclonal antibodies against IL-6, are approved to treat different types of arthritis and control other inflammatory conditions.
“We’re not sure why the brain produces a protein signal that is so damaging to muscle function in so many different categories of disease,” Johnson argues. “If we want to speculate on possible reasons why this process has stayed with us throughout human evolution, despite the damage it causes, it could be a way for the brain to reallocate resources to itself while fighting off disease. We need more research to better understand this process and its consequences throughout the body.”
“In the meantime, we hope our study will encourage further clinical research into this pathway and to see whether existing treatments that block various parts of it can help the many patients who experience this type of debilitating muscle fatigue,” he concluded.
Source: Washington University in St. Louis
