Uncontrolled inflammation plays a role in muscle loss and weakness in many diseases, including rheumatoid arthritis. A new study suggests that when exercised, our muscles have an innate ability to reduce this harmful inflammation.
Inflammation is a mixed blessing. In the short term, it tackles infections and promotes muscle regeneration after an injury.
Persistent inflammation, on the other hand, plays a part in many illnesses, including rheumatoid arthritis and sarcopenia, which is muscle wasting associated with aging.
Fortunately, a wealth of evidence suggests that regular exercise can help counter the effects of inflammation in aging, also known as “inflammaging.”
In particular, staying fit and active reduces the long-lasting, or chronic, inflammation known to increase the risk of many diseases that affect older people.
Exactly how active muscle fibers quench inflammation has been unclear, however.
Most researchers had assumed that inflammation is reduced by molecular cross-talk between muscle fibers and other cells in muscle tissue, such as fat cells and immune cells.
But a new study from biomedical engineers at Duke University, in Durham, NC, suggests that muscle cells are perfectly capable of controlling inflammation by themselves.
The research has been published in the journal Science Advances.
“Lots of processes are taking place throughout the human body during exercise, and it is difficult to tease apart which systems and cells are doing what inside an active person,” explains Nenad Bursac, a professor of biomedical engineering at Duke and the senior author of the research paper.
To focus exclusively on muscle cells, therefore, the team grew human muscle that was devoid of other types of cell.
Prof. Bursac’s lab has been growing skeletal muscle in petri dishes for nearly a decade. They can vary the cellular makeup of the muscle, which is fully functional and can contract.
“Our engineered muscle platform is modular, meaning we can mix and match various types of cells and tissue components if we want to,” says Prof. Bursac. “But in this case, we discovered that the muscle cells were capable of taking anti-inflammatory actions all on their own.”
To simulate chronic inflammation, for 7 days the researchers doused their lab-grown muscle with interferon-gamma, an immune signaling molecule that promotes inflammation and has been linked to muscle wasting and dysfunction.
As expected, the muscle fibers shrank and became weaker.
Next, to simulate exercise, the scientists sent a tiny electrical current through the muscle.
Remarkably, over time, the current stimulated muscle growth. It also reduced the muscle-wasting and weakening effects of interferon-gamma.
The scientists managed to pinpoint the exact molecular pathway responsible for these effects on inflammation in muscles. They showed that interferon-gamma stimulates this pathway, whereas exercise inhibits it.
“Not only did we confirm that interferon-gamma primarily works through a specific signaling pathway, we showed that exercising muscle cells can directly counter this pro-inflammatory signaling — independent of the presence of other cell types or tissues,” says Zhaowei Chen, a postdoctoral researcher in Prof. Bursac’s lab and the first author of the paper.
The research has more than mere curiosity value — it may influence the treatment of patients.
Two drugs approved for rheumatoid arthritis, called tofacitinib (Xeljanz) and baricitinib (Olumiant), work by inhibiting the same inflammatory pathway.
A recently published pilot study hints that baricitinib may also be a safe and effective anti-inflammatory treatment for patients hospitalized with COVID-19.
As a final test of their findings, the researchers at Duke applied each drug in turn to their lab-grown muscle.
They found that both drugs blocked the effects of interferon-gamma, and in the process prevented muscle wasting and weakness.
In addition to exploring the anti-inflammatory effects of exercise, the authors propose that scientists could use lab-grown muscle to test the ability of other drugs to prevent wasting and chronic inflammation.
Prof. Bursac explains:
“These results show just how valuable lab-grown human muscles might be in discovering new mechanisms of disease and potential treatments. There are notions out there that optimal levels and regimes of exercise could fight chronic inflammation while not overstressing the cells. Maybe with our engineered muscle, we can help find out if such notions are true.”