Brain Inflammation and Muscle Weakness Linked by Signaling Axis

Infections and neurodegenerative diseases cause inflammation in the brain. But for unknown reasons, patients with brain inflammation often develop muscle problems that seem to be independent of the central nervous system. Studies by researchers at Washington University School of Medicine in St. Louis have now discovered that brain inflammation releases a specific protein that travels from the brain to the muscles and causes a loss of muscle function.

The preclinical study, in fruit flies and mice, also identified ways to block this process, which could have implications for treating or preventing the muscle wasting sometimes associated with inflammatory diseases—including bacterial infections—Alzheimer’s disease and long COVID.

“We are interested in understanding the very deep muscle fatigue that is associated with some common illnesses,” said senior author Aaron Johnson, PhD, an 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 capacity to move and function normally.”

Johnson and colleagues reported on their findings in Science Immunology, in a paper titled “Infection and chronic disease activate a systemic brain-muscle signaling axis.” In their report the team concluded, “Our study argues that infections and chronic diseases activate a conserved IL-6–mediated systemic brain-muscle signaling axis, which could be a therapeutic target to improve muscle outcomes in affected patients.”

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

To investigate the effects of brain inflammation on muscle function, the researchers modeled three different types of diseases—an E. coli bacterial infection, a SARS-CoV-2 viral infection and Alzheimer’s. When the brain is exposed to inflammatory proteins characteristic of these diseases, damaging chemicals called reactive oxygen species (ROS) build up. The 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.

The researchers found that IL-6 in mice—and the corresponding protein in fruit flies—reduced energy production in muscles’ mitochondria, the energy factories of cells. “ROS induced expression of the cytokine Unpaired 3 (Upd3) in Drosophila and its ortholog IL-6 in mice,” the team stated. “CNS-derived Upd3/IL-6 activated the JAK-STAT pathway in skeletal muscle, which caused muscle mitochondrial dysfunction and impaired motor function.” They concluded, “In summary, we found multiple CNS stressors, including bacterial infection, SARS-CoV-2 protein expression, and neurotoxic protein expression, activate a systemic brain-muscle signaling axis that causes mitochondrial dysfunction in skeletal muscle.”

 

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.”

Johnson, along with collaborators at the University of Florida and first author Shuo Yang, PhD—who did this work as a postdoctoral researcher in Johnson’s lab—make the case that the same processes are likely relevant in people. The bacterial brain infection meningitis is known to increase IL-6 levels and can be associated with muscle issues in some patients, for instance. Among COVID-19 patients, inflammatory SARS-CoV-2 proteins 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 increased levels of IL-6 in the blood as well as muscle weakness.

The study pinpoints potential targets for preventing or treating muscle weakness related to brain inflammation. Several therapeutics already approved by the Food and Drug Administration for other diseases can block this JAK-STAT pathway, the team pointed out. JAK inhibitors as well as several monoclonal antibodies against IL-6 are approved to treat various types of arthritis and manage other inflammatory conditions. “IL-6 inhibitors have been used to treat autoimmune diseases such as rheumatoid arthritis, and clinical trials are ongoing to expand the inflammatory disorders that can be targeted with IL-6 inhibitors,” the researchers stated.

“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.

“In the meantime, we hope our study encourages more 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. Acknowledging limitations of their study, and noting results from previous clinical studies using IL-6 inhibitors or JAK inhibitors, the team further concluded, “These clinical results argue that systemic treatment with IL-6 and JAK inhibitors could inhibit changes to muscle performance induced by the brain-muscle signaling axis and prevent muscle dysfunction associated with chronic and infectious diseases.”