Infectious or chronic diseases such as long COVID, Alzheimer’s disease and traumatic brain injury can cause inflammation in the brain, or neuroinflammation, that weakens muscles. While scientists are aware of this link between inflammation and muscle weakness, the molecules and processes involved have been unclear.

In our research, our team of neuroscientists and biologists uncovered the hidden conversation between the brain and muscles that triggers muscle fatigue, and potential ways to treat it.

Neuroinflammation and muscle fatigue

Neuroinflammation results when your central nervous system – the brain and spine – activates its own immune system to protect itself against infection, toxins, neurodegeneration and traumatic injury. Neuroinflammatory reactions primarily occur in the brain. But for unknown reasons, patients also experience many symptoms outside the central nervous system, such as debilitating fatigue and muscle pain.

To solve this puzzle, we studied brain inflammation in the context of three different diseases: bacterial infection in E. coli-induced meningitis; viral infection in COVID-19; and neurodegeneration in Alzheimer’s disease. Then, we analyzed how these immune changes affect muscle performance.

We measured immune changes in the brains of fruit flies and mice infected with live bacteria, viral proteins or neurotoxic proteins. After the initial accumulation of toxic molecules in the brain that commonly increase in response to stresses such as infection, the brain produces high levels of cytokines – chemicals that activate the immune system – that are released into the body. When these cytokines travel to muscles, they activate a series of chemical reactions that disrupts the ability of the powerhouse of cells – mitochondria – to produce energy.

Though the result of these immune changes doesn’t seem to damage muscle fibers, it does cause fatigue. When we measured the muscle performance of these animals after giving them treatments to offset the effects of immune activation, we found that both flies and mice moved significantly less in response to manual or mechanical stimuli compared with those that were not infected. This indicated that the animals had reduced endurance.

Conversations between brain and muscle

Our findings suggest that the muscle fatigue that results from infection or chronic illness is caused by a brain-to-muscle communication pathway that depletes energy in muscles without disrupting their structure or integrity. Unlike traditional explanations for muscle dysfunction that focus on causes outside the brain, such as damage to the muscle fibers, this pathway directly causes fatigue.

Since the key cytokine involved in brain-to-muscle communication has been preserved throughout evolution across different species, we believe this signaling pathway could represent a universal mechanism the brain uses to claim and reallocate energy to fight against infection.

Since we studied the brain-muscle axis only in the context of simplified models, we don’t know whether it applies to more complex conditions such as fibromyalgia or chronic fatigue syndrome. We also don’t know how impaired energy production in muscles correlates with impaired energy production in the brain.

Furthermore, the brain-muscle axis works through a series of interconnected steps. But the precise mechanism of this communication and the potential involvement of other cytokines are unknown.

Muscle fatigue common across disease

Muscle weakness and fatigue are common symptoms in multiple diseases, ranging from bacterial and viral infections to chronic disorders and neurodegenerative conditions. These symptoms are distressing and reduce the quality of life of millions of people worldwide.

For instance, most of the 65 million people around the world struggling with long COVID experience disabling fatigue lasting from months to years.

Similarly, reduced muscle strength is a common symptom of early stage Alzheimer’s disease, a condition that affects at least 50 million people globally.

Better understanding of how neuroinflammation causes muscle fatigue can lead to potential treatments that improve muscle function.

New treatments on the horizon

Our work suggests that targeting the brain-muscle axis could offer new treatment strategies for muscle fatigue.

Currently, we are testing neutralizing antibodies – proteins that bind to and inhibit the function of cytokines – in mice with neuroinflammation. These FDA-approved treatments specifically target cytokines secreted by the brain and prevent signaling to muscle. We are interested in identifying which neutralizing antibodies, or combinations of antibodies, prevent muscle fatigue in mice.

We are also planning a long COVID clinical trial to profile cytokine levels in patients. It is unclear whether other COVID-19 proteins can also trigger neuroinflammation and muscle fatigue. Recent evidence suggests that long COVID may be linked to lingering viral particles in several organs, including the brain, even months after infection. However, it is uncertain whether and how this might be connected with the high levels of cytokines seen in long COVID.

With further development, targeting the brain-muscle axis could be a useful treatment for people suffering with long COVID and other diseases that cause brain inflammation.

Diego E. Rincon-Limas receives funding from National Institutes on Aging.

Aaron N. Johnson receives funding from the National Institutes of Health.