Brain Inflammation Study Reveals Pathways To Combat Muscle Fatigue in Long COVID and Alzheimer's
A study has identified how brain inflammation triggers muscle weakness, revealing ways to block fatigue in disease.

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Brain inflammation results in the release of a specific protein that travels from the brain to the muscles resulting in fatigue and loss of muscle function, a new study published in the journal Science Immunology has found.
Performed in fruit flies and mice, the study also identified ways to block this process. This offers new hope for treating and preventing the muscle pain and fatigue associated with inflammatory diseases such as Alzheimer's and long COVID.
Brain disruption regulates muscle performance
Infectious diseases, chronic conditions, such as Alzheimer′s disease and normal aging all induce neuroinflammation, which disrupts neural function through changes in neuronal structure or survivability. Neuroinflammation primarily targets cells in the central nervous system (CNS), however, for unknown reasons patients with brain inflammation often develop muscle problems independent of the CNS.
Researchers at Washington University School of Medicine in St. Louis were interested in further understanding how inflammatory signals in the brain are communicated to muscle cells. They found that neuroinflammation results in messenger proteins being sent from the brain through the bloodstream which subsequently reduce energy levels in skeletal muscle.
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Subscribe for FREE“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,” said Dr. Aaron Johnson, senior author of the study and associate professor of developmental biology at Washington University School of Medicine in St. Louis.
The researchers modeled three types of diseases — an E. coli bacterial infection, a SARS-CoV-2 viral infection and Alzheimer’s — to investigate the impact of CNS stressors on motor function. They found that when the brain is exposed to inflammatory proteins characteristic of these diseases, damaging chemicals called reactive oxygen species accumulate in the brain. These species induce expression of interleukin-6 (IL-6) in mice – and the corresponding protein in fruit flies. These proteins activate the JAK-STAT pathway in skeletal muscle, which causes muscle mitochondrial dysfunction and impaired motor function.
What is the JAK-STAT pathway?
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway is a key communication method between cells and proteins and is essential for numerous developmental and homeostatic processes. JAK-STAT-mediated downstream events include hematopoiesis, immune fitness, tissue repair, inflammation, apoptosis and adipogenesis. Dysregulation of the JAK-STAT pathway has been associated with various cancers and autoimmune diseases.
The researchers showed that flies and mice which had COVID-associated proteins in the brain had reduced motor function. Flies with these proteins did not climb as well as the control group and mice did not run as much or as well. A similar effect was observed when the brain was exposed to bacterial-associated protein 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,” said Johnson.
While these experiments were conducted in mice and flies, the researchers suggest the same processes are likely relevant in people. For example, 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.
Therapeutic targets to treat muscle dysfunction
The discovery that activation of the JAK-STAT pathway in the muscle causes the reduced energy production of the mitochondria hints at possible ways for preventing or treating muscle weakness related to brain inflammation. IL-6 inhibitors have been used to treat autoimmune diseases, including various types of arthritis, and clinical trials are ongoing to expand the inflammatory disorders that can be targeted with IL-6 inhibitors.
“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,” the researchers concluded.
The question of why the brain produces a signal that damages muscle function when exposed to these diseases remains. The researchers speculate that it could be a way for the brain to reallocate resources to itself as it fights off disease, but emphasize that more research is needed 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,” Johnson said.
Reference: Yang S, Tian M, Dai Y, et al. Infection and chronic disease activate a systemic brain-muscle signaling axis. Science Immunology. 2024. doi: 10.1126/sciimmunol.adm7908
This article is a rework of a press release. Material has been edited for length and content.