Muscle exercise fights chronic inflammation on its own

Biomedical engineers at Duke University have shown that human muscle has an innate ability to prevent the damaging effects of chronic inflammation when exercised. The discovery was made possible through the use of human muscles developed in the laboratory, demonstrating the potential power of the unprecedented platform in such research ventures.

The results appear online on January 22 in the magazine Advances in Science.

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

Inflammation is not inherently good or bad. When the body is injured, an initial low-level inflammation response removes waste and helps rebuild tissue. At other times, the immune system overreacts and creates an inflammatory response that causes damage, such as the often deadly cytokine storms caused by some cases of COVID-19. In addition, there are diseases that lead to chronic inflammation, such as rheumatoid arthritis and sarcopenia, which can cause muscle wasting and weaken your 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 loss and dysfunction. Although previous research in humans and animals has shown that exercise can help to mitigate the effects of inflammation in general, it has been difficult to distinguish what role muscle cells themselves can play, let alone how they interact with specific aggressive molecules, such as interferon gamma .

“We know that chronic inflammatory diseases induce muscle atrophy, but we wanted to see if the same thing would happen to our human muscles developed in a petri dish,” said Zhaowei Chen, a postdoctoral researcher in the Bursac laboratory and the article’s first author. “Not only have we confirmed that gamma interferon works primarily through a specific signaling pathway, but we have shown that muscle cells in exercise can directly combat this proinflammatory signaling regardless of the presence of other types of cells or tissues.”

To prove that the muscle alone is capable of blocking the destructive powers of gamma interferon, Bursac and Chen turned to a designed muscle platform that the laboratory has been developing for almost a decade. They were the first to develop functional, skeletal human muscles contracted in a Petri dish, and since then, the laboratory has improved its processes, for example, by adding immune cells and stem cell reservoirs to the recipe.

In the current study, researchers took these fully grown 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 became smaller and lost much of its strength.

The researchers then applied gamma interferon again, but this time they also placed the muscle on a simulated exercise regime, stimulating it with a pair of electrodes. Although they expected the procedure to induce some muscle growth, as shown in their previous studies, 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 were directly opposed to the pro-inflammatory signal induced by gamma interferon, which we did not expect to happen,” said Bursac. “These results show how valuable human muscles grown in the laboratory can be in discovering new disease mechanisms and potential treatments. There are notions out there that ideal levels and regimes of exercise can fight chronic inflammation without overloading cells. Perhaps with our muscle engineering, we can help find out if these notions are true. ”