When you exercise, you can fight chronic inflammation on its own.

Biomedical engineers at Duke University have shown that human muscle has an innate ability to ward off the harmful effects of chronic inflammation when exercised. The discovery was made possible through laboratory-grown, engineered human muscles, demonstrating the potential power of the first-of-its-kind platform in such research efforts.

The results will be published in the journal on 22 January Scientific progress.

“Many processes take place through the human body during exercise, and it’s difficult to tell which systems and cells are doing within an active person,” says Nenad Bursac, professor of biomedical engineering at Duke. “Our designed muscle platform is modular, which means we can mix and match different types of cells and tissue components as we wish. But in this case, we discovered that the muscle cells are capable of performing anti-inflammatory actions on their own.”

Inflammation is not inherently good or bad. If the body is injured, an initial low-level inflammatory response removes debris and helps rebuild the tissue. Other times the immune system overreacts and creates an inflammatory reaction that causes damage, such as the often fatal cytokine storms caused by some cases of COVID-19. And then there are diseases that lead to chronic inflammation, such as rheumatoid arthritis and sarcopenia, which can cause muscles to be wasted and the ability to contract to weaken.

Among many molecules that can cause inflammation, one pro-inflammatory molecule in particular, interferon gamma, is associated with different types of muscle wasting and dysfunction. While previous research in humans and animals has shown that exercise can help reduce the effects of inflammation in general, it was difficult to discern what role the muscle cells themselves may play, let alone how they interact with specific affected molecules, such as interferon gamma, has interaction. .

“We know that chronic inflammatory diseases cause muscle atrophy, but we wanted to see if the same thing would happen to our manipulated human muscles that grew in a Petri dish,” said Zhaowei Chen, a postdoctoral researcher in Bursac’s laboratory and first author of the article, said. . “We not only confirmed that interferon gamma works primarily through a specific signaling pathway, but we have shown that exercising muscle cells can directly counteract this pro-inflammatory signal, independent of the presence of other cell types or tissues.”

To prove that muscle alone can block the destructive forces of interferon gamma, Bursac and Chen have turned to a designed muscle platform that the laboratory has been developing for nearly a decade. They first cultured contractile, functional human skeletal muscle in a Petri dish, and since then the laboratory has improved its processes by adding, for example, immune cells and reservoirs of stem cells to the recipe.

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

The researchers then again applied interferon gamma, but this time also placed the muscle through a simulated exercise regimen by stimulating it with a few electrodes. While they expected the procedure to cause some muscle growth, as evidenced by their previous studies, they were surprised to discover that it prevented the effects of chronic inflammation almost completely. 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 interferon gamma, which we would not expect,” Bursac said. “These results show how valuable human muscle can be in laboratories to discover new mechanisms of disease and potential treatments. There are ideas out there that optimal levels and exercise systems can fight chronic inflammation while not over-emphasizing the cells. Maybe with our designers muscles, can help us find out if such beliefs are true. ‘