Research has demonstrated how brain inflammation can lead to severe muscle weakness in various conditions like viral and bacterial infections, as well as Alzheimer’s disease. The study, conducted on fruit flies and mice, has also identified strategies to inhibit this process. These findings could potentially help in managing muscle wasting commonly seen in inflammatory diseases such as bacterial infections, Alzheimer’s disease, and long COVID.
Infections and neurodegenerative diseases often trigger inflammation in the brain. Interestingly, patients with brain inflammation frequently experience muscle problems that appear to be unrelated to the central nervous system. Scientists at Washington University School of Medicine in St. Louis have uncovered how brain inflammation releases a specific protein that travels from the brain to the muscles, leading to a loss of muscle function.
The study, involving fruit flies and mice, presented ways to disrupt this process, offering potential implications for addressing muscle wasting in inflammatory diseases. This study was published on July 12 in the journal Science Immunology.
“We are keen on understanding the profound muscle fatigue associated with certain common illnesses,” explained senior author Aaron Johnson, PhD, an associate professor of developmental biology. “Our research indicates that when individuals fall ill, messenger proteins from the brain circulate in the bloodstream, reducing energy levels in skeletal muscle. This goes beyond just a lack of motivation to move due to feeling unwell. These processes diminish energy levels in skeletal muscle, limiting the ability to move and function normally.”
To investigate how brain inflammation affects muscle function, researchers simulated three different types of diseases – an E. coli bacterial infection, a SARS-CoV-2 viral infection, and Alzheimer’s. Exposure of the brain to inflammatory proteins characteristic of these diseases led to the accumulation of harmful chemicals known as reactive oxygen species. These reactive oxygen species prompted brain cells to produce interleukin-6 (IL-6), an immune-related molecule that travels throughout the body via the bloodstream. The study revealed that IL-6 in mice – and its equivalent protein in fruit flies – reduced energy production in the mitochondria of muscles, which are the cell’s energy factories.
“Flies and mice with brain presence of COVID-associated proteins displayed reduced motor function – the flies showed decreased climbing ability, and the mice exhibited reduced running activity compared to control mice,” Johnson noted. “Similar impacts on muscle function were observed when the brain was exposed to bacterial-associated proteins and the Alzheimer’s protein amyloid beta. Moreover, there is evidence that this effect can persist chronically. Even after swift clearance of an infection, reduced muscle performance continued for many days in our experiments.”
Johnson, in collaboration with partners at the University of Florida and first author Shuo Yang, PhD – who conducted this research as a postdoctoral scholar in Johnson’s lab – suggested that these processes likely apply to humans as well. For instance, meningitis, a bacterial brain infection, is known to elevate IL-6 levels and might be linked to muscle problems in some patients. In COVID-19 cases, inflammatory SARS-CoV-2 proteins have been detected in the brain during autopsies, and many long COVID patients report severe fatigue and muscle weakness long after clearing the initial infection. Patients with Alzheimer’s disease also exhibit increased IL-6 levels in the blood alongside muscle weakness.
The study pinpointed potential targets to manage muscle weakness related to brain inflammation. The researchers found that IL-6 activates the JAK-STAT pathway in muscles, leading to decreased energy production in the mitochondria. There are already FDA-approved therapeutics that can block this pathway, such as JAK inhibitors and several monoclonal antibodies targeting IL-6, which are used to treat various forms of arthritis and manage other inflammatory conditions.
“It remains unclear why the brain produces a protein signal that is so harmful to muscle function across different disease categories,” Johnson remarked. “One speculative reason could be that it’s a mechanism for the brain to divert resources to itself while combating illness. Further research is needed to comprehend this process better and its implications throughout the body.
“In the interim, we hope that our study encourages further clinical investigation into this pathway and whether existing treatments targeting different components of it can benefit the numerous patients experiencing this debilitating muscle fatigue,” he added.
