Infections and neurodegenerative diseases cause inflammation in the brain. But for unknown reasons, patients with brain inflammation often develop muscle problems that appear to be independent of the central nervous system. Now, researchers at Washington University School of Medicine in St. Louis have revealed how brain inflammation releases a specific protein that travels from the brain to the muscles and causes a loss of muscle function.
The study, in fruit flies and mice, also identified ways to block this process, which could have implications for treating or preventing muscle wasting sometimes associated with inflammatory diseases, including bacterial infections, Alzheimer’s disease and long COVID.
The study is 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, PhD, 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 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.”
To investigate the effects of brain inflammation on muscle function, the researchers modeled three different types of diseases: a E. coli Bacterial infection, SARS-CoV-2 viral infection, and Alzheimer’s. When the brain is exposed to inflammatory proteins characteristic of these diseases, harmful chemicals called reactive oxygen species build up. Reactive oxygen species cause brain cells to produce an immune-related molecule called interleukin-6 (IL-6), which travels throughout the body via the bloodstream. Researchers found that IL-6 in mice (and the corresponding protein in fruit flies) reduced energy production in muscle mitochondria, the energy factories of cells.
“Flies and mice that had COVID-associated proteins in their brains showed reduced motor function: Flies didn’t climb as well as they should, and mice didn’t run as well or as long as control mice,” Johnson said. “We saw similar effects on muscle function when the brain was exposed to bacteria-associated proteins and the Alzheimer’s amyloid beta protein. We also see evidence that this effect can become chronic. Even if an infection clears up quickly, reduced muscle performance lingers for many days afterward in our experiments.”
Johnson, along with collaborators at the University of Florida and first author Shuo Yang, PhD (who performed this work as a postdoctoral researcher in Johnson’s lab), argue that the same processes are likely relevant in people. Meningitis, a bacterial brain infection, is known to increase IL-6 levels and may be associated with muscle problems in some patients, for example. Among COVID-19 patients, inflammatory proteins from SARS-CoV-2 have been found in the brain during autopsy, and many long-COVID patients report extreme fatigue and muscle weakness even long after the initial infection has cleared. Patients with Alzheimer’s disease also show elevated levels of IL-6 in their blood, as well as muscle weakness.
The study points to potential targets for preventing or treating muscle weakness linked to brain inflammation. The researchers found that IL-6 activates what’s called the JAK-STAT pathway in muscle, which is what causes reduced energy production from mitochondria. Several treatments already approved by the Food and Drug Administration for other diseases can block this pathway. JAK inhibitors, as well as several monoclonal antibodies against IL-6, are approved to treat several types of arthritis and control other inflammatory conditions.
“We’re not sure why the brain produces a protein signal that is so detrimental to muscle function in so many different disease categories,” Johnson said. “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 as it fights 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 whether existing treatments that block various parts of it can help the many patients who experience this type of debilitating muscle fatigue,” he said.