DURHAM, NC—Biomedical engineers at Duke University have demonstrated that human muscle has the ability to negate the effects of chronic inflammation when exercised. Researchers discovered this with the use of lab-grown, engineered human muscle. The study has been published in 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,” noted Nenad Bursac, professor of biomedical engineering at Duke. “Our engineered muscle platform is modular, meaning we can mix and match various types of cells and tissue components if we want to. But in this case, we discovered that the muscle cells were capable of taking anti-inflammatory actions all on their own.”
Inflammation isn’t inherently negative — when the body is injured, an initial low-level inflammation response clears away debris and helps tissue rebuild. But the immune system can also overreact and create an inflammatory response that causes damage. Diseases like rheumatoid arthritis and sarcopenia can also lead to chronic inflammation, which can weaken the muscle’s ability to contract.
Interferon gamma in particular is associated with various types of muscle wasting and dysfunction. Previous research in humans and animals has proven that exercise can help to mitigate the effects of inflammation, but it has been difficult to distinguish what role the muscle cells themselves might play, and how they interact with specific molecules like interferon gamma.
“We know that chronic inflammatory diseases induce muscle atrophy, but we wanted to see if the same thing would happen to our engineered human muscles grown in a Petri dish. 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,” added Zhaowei Chen, a postdoctoral researcher in Bursac’s laboratory, and first author of the paper.
To prove that muscle is capable of blocking interferon gamma’s destructive powers by itself, Bursac and Chen used an engineered muscle platform that the laboratory has been developing for nearly a decade. The lab has been improving its processes by doing things like adding immune cells and stem cell reservoirs to the recipe.
For the current study, the researchers took these fully functional, lab-grown muscles and bombarded them with relatively high levels of interferon gamma for seven days to mimic the effects of chronic inflammation. As expected, the muscle shrank and lost much of its strength.
The researchers then applied interferon gamma again, and put the muscle through a simulated exercise regime via electrode stimulation. The team expected the procedure to induce some muscle growth as it had for previous studies, but they were surprised to discover that the simulated exercise almost completely prevented the effects of chronic inflammation.
“When co-applied with IFN-γ, a 7-day intermittent exercise-mimetic E-stim had pronounced protective effects on myobundles,” states the article. “Beside its well-established hypertrophic and strengthening effects (24, 43), the exercise-mimetic E-stim (24) partially reduced IFN-γ–induced STAT1 up-regulation, established using selective JAK/STAT inhibitors to be the dominant proinflammatory mediator of IFN-γ action in myobundles.”
Researchers proved that simulated exercise inhibited a specific molecular pathway in muscle cells. Two drugs used to treat rheumatoid arthritis that block the same pathway — tofacitinib and baricitinib — had the same anti-inflammatory effect.
“Application of the inhibitors to IFN-γ–treated myobundles significantly decreased pSTAT1 expression to near-naïve levels (Fig. 6, G and H), without altering the IFN-γ–induced increase in STAT1 expression (fig. S7F). Consequently, the IFN-γ–induced increase in STAT1 activity (pSTAT1/STAT1) was fully prevented by co-application of the inhibitors, explaining their strong protective effects on myobundle function,” the article continues. “Together, these results established that the adverse effect of IFN-γ on human myobundles was predominantly mediated via up-regulation of JAK/STAT1 signaling rather than changes in alternative signaling pathways (39).”
The article points out that the engineered muscle platform will be useful for muscle inflammation studies, and for explicating the anti-inflammatory role of exercise.
“When exercising, the muscle cells themselves were directly opposing the pro-inflammatory signal induced by interferon gamma, which we did not expect to happen. These results show just how valuable lab-grown human muscles might be in discovering new mechanisms of disease and potential treatments,” Bursac explained. “There are notions out there that optimal levels and regimes of exercise could fight chronic inflammation while not over-stressing the cells. Maybe with our engineered muscle, we can help find out if such notions are true.”