Muscle exercise alone fights chronic inflammation

Biomedical engineers at Duke University have shown that human muscle has an innate ability to ward off the damaging effects of chronic inflammation during exercise. The discovery was made possible through the use of human muscles grown in the laboratory, demonstrating the potential power of the one-of-a-kind platform in these research efforts.

The results appear online January 22 in the journal Scientific advances.

“Many processes take place throughout the human body during exercise, and it is difficult to determine which systems and cells do what inside an active person,” said Nenad Bursac, professor of biomedical engineering at Duke. . “Our artificial muscle platform is modular, which means we can mix and match different types of cells and tissue components if we want to. But in this case, we found that the muscle cells were able to take anti-inflammatory actions on their own. “

Inflammation is neither good nor bad per se. When the body is injured, an initial low-level inflammatory response removes debris and helps rebuild tissue. Other times, the immune system overreacts and creates an inflammatory response that causes damage, like the often fatal cytokine storms caused by some cases of COVID-19. And then there are diseases that lead to chronic inflammation, like rheumatoid arthritis and sarcopenia, which can lead to muscle wastage and weaken its ability to contract.

Among many molecules that can cause inflammation, one pro-inflammatory molecule in particular, gamma interferon, has been associated with various types of muscle wasting and dysfunction. While previous research in humans and animals has shown that exercise can help lessen the effects of inflammation in general, it has been difficult to distinguish the role that muscle cells themselves might play, and even less how they interact with specific offending molecules, such as gamma interferon. .

“We know that chronic inflammatory diseases induce muscle atrophy, but we wanted to see if the same would happen to our artificial human muscles grown in a petri dish,” said Zhaowei Chen, postdoctoral researcher at the Bursac lab and first author of the article. “Not only have we confirmed that gamma interferon works primarily through a specific signaling pathway, but we have shown that exercise in muscle cells can directly counteract this pro-inflammatory signaling regardless of the presence of other cell types or fabrics. “

To prove that muscle alone is able to block the destructive powers of gamma interferon, Bursac and Chen turned to an engineered muscle platform that the lab has been developing for nearly a decade. They were the first to develop functioning, contracting human skeletal muscle in a petri dish, and since then the lab has improved its processes by adding, for example, immune cells and stem cell reservoirs to the recipe.

In the present study, the researchers took these fully functional, lab-grown muscles and flooded them with relatively high levels of gamma interferon for seven days to mimic the effects of long-lasting chronic inflammation. As expected, the muscle got smaller and lost much of its strength.

The researchers then applied the gamma interferon again, but this time they also put the muscle through a simulated exercise regimen by stimulating it with a pair of electrodes. While they expected the procedure to induce some muscle growth, as their previous studies show, they were surprised to find that it almost completely prevented the effects of chronic inflammation. They then showed that simulated exercise inhibited a specific molecular pathway in muscle cells and that two drugs used to treat rheumatoid arthritis, tofacitinib and baricitinib, which block the same pathway, had the same anti-inflammatory effect.

“During exercise, the muscle cells themselves directly opposed the pro-inflammatory signal induced by gamma interferon, which we did not expect,” Bursac said. “These findings show just how useful human muscles grown in the lab could be in uncovering new disease mechanisms and potential treatments. There are notions that optimal levels and exercise regimens could fight chronic inflammation. without overloading the cells. Perhaps with our engineering. muscle, we can help find out if such notions are true. ”