Working Out May Combat Inflammation in Newly-Discovered Ways

Exercising muscles may block interferon gamma (IFN-γ), an inflammatory cytokine.

Posted Jan 26, 2021

I T A L O/Shutterstock
Source: I T A L O/Shutterstock

First-of-its-kind research performed on lab-grown muscle tissue suggests that when human muscle cells are stimulated during exercise, it triggers a complex chain reaction that may combat chronic inflammation by blocking a pro-inflammatory cytokine called interferon gamma (IFN-γ). This Duke University study (Chen et al., 2021) was published on January 22 in Science Advances.

For this study, a team of researchers from Duke's Department of Biomedical Engineering, led by Nenad Bursac and Zhaowei Chen, used an in vitro tissue-engineered model of human skeletal muscle (i.e., myobundles) "to investigate the interplay between IFN-γ and exercise-mimetic stimulation in inflammatory response of human skeletal muscle." The Bursac Lab has been developing novel ways to grow functional human muscles that can contract in a Petri dish for nearly a decade.

The researchers emphasize that in and of itself, inflammation isn't inherently "good" or "bad." For example, low-level, acute inflammation serves a vital role in clearing away debris and helping tissue repair after an injury. However, when the immune system overreacts, hyperactive inflammatory responses can trigger cytokine storms, which can be deadly. 

Systemic inflammation, which is the hallmark of diseases like rheumatoid arthritis and sarcopenia, inhibits muscles' ability to flex and contract, which can cause skeletal muscles to weaken and atrophy.

 Image credited to Zhaowei Chen, Duke University (labeled for reuse)
Long, thin, well-defined muscle fibers (top left) are in shambles after prolonged inflammation (top right) but maintain their structure (bottom left) and strength (bottom right) when exercised during the inflammation.
Source: Image credited to Zhaowei Chen, Duke University (labeled for reuse)

Previous research in animals and humans has shown that exercise helps to mitigate harmful systemic inflammation. That said, until the advent of lab-grown myobundles, it was difficult for scientists to pinpoint precisely how exercising a muscle affects pro-inflammatory cytokines such as interferon gamma.

In the first phase of their most recent (2021) study, Bursac's team inundated fully-functioning lab-grown myobundles in a Petri dish with interferon gamma for seven consecutive days; continuous exposure to high levels of IFN-γ mimics the effects of long-lasting chronic inflammation on human skeletal muscle.

"As expected, the muscle got smaller and lost much of its strength," the researchers explain in a news release. "Among many molecules that can cause inflammation, one pro-inflammatory molecule in particular, interferon gamma, has been associated with various types of muscle wasting and dysfunction."

In the second phase of this experiment, the researchers inundated the same muscle tissue with interferon gamma again. But this time, they used a pair of electrodes that stimulated the muscle to contract in a way that simulated a strength-training workout. Although Chen et al. expected the exercise-like stimulation of a myobundle to induce muscle growth, "they were surprised to discover that it almost completely prevented the effects of the chronic inflammation."

Interestingly, another Petri-dish experiment showed that two commonly used rheumatoid arthritis drugs blocked the same pro-inflammatory pathways and had the same anti-inflammatory effect as exercise.

"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," senior author Nenad Bursac said in the news release. "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."

"When exercising, the muscle cells themselves were directly opposing the pro-inflammatory signal induced by interferon gamma, which we did not expect to happen," he added. "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 [muscle] cells," Bursac concludes. "Maybe with our engineered muscle, we can help find out if such notions are true."

Image credited to Zhaowei Chen, Duke University via EurekAlert (labeled for reuse)

References

Zhaowei Chen, Binjie Li, Ren-Zhi Zhan, Lingjun Rao, Nenad Bursac. "Exercise Mimetics and JAK Inhibition Attenuate IFN-γ-induced Wasting in Engineered Human Skeletal Muscle." Science Advances (First published: January 22, 2021) DOI: 10.1126/sciadv.abd9502

Lauran Madden, Mark Juhas, William E. Kraus, George A. Truskey, Nenad Bursac. "Bioengineered Human Myobundles Mimic Clinical Responses of Skeletal Muscle to Drugs." eLife (First published: January 09, 2015) DOI: 10.7554/eLife.04885.001