Lab-grown human muscle is teaching us how to live longer

Inflammation is a vital, sometimes life-saving, feature of the immune system. It's one of the first steps of the body's healing process, helping remove or repair harmful stimuli.

But when inflammation lingers for months or years, it can cause devastating damage — wasting away muscles and contributing to chronic inflammatory diseases including stroke, chronic respiratory diseases, and cancer. Chronic inflammation can be caused by several factors, including untreated injury, chronic stress, and autoimmune disorders.

Human clinical trials examining chronic inflammation suggest exercise, among other strategies, can lower pro-inflammatory molecules and cytokines, and combat some of these negative health outcomes. But exactly how exercise induces this anti-inflammatory effect hasn't been clear.

By engineering and experimenting on lab-grown human muscle tissue, researchers recently discovered exercising muscles have an innate ability to block certain pro-inflammatory cytokines that cause damage related to chronic inflammation. This finding is published in the journal Science Advances.

Over time, this muscular "self-defense mechanism" may help people preserve muscle mass and stave off some of the most common, deadly diseases plaguing modern humans.

"We found that exercising muscle cells can autonomously prevent inflammatory effects," study co-author Nenad Bursac tells Inverse. Bursac is a biomedical engineer at Duke University.

"Exercise directly attenuates a molecular signaling pathway upregulated by inflammation."

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HOW THIS AFFECTS LONGEVITY — Bursac and his team were the first scientists to engineer contracting, functional human skeletal muscle in a Petri dish, creating a muscle platform called the human myobundle system. The platform presents a unique opportunity to examine exercise and inflammation in a hypercontrolled environment.

In this study, the team examined how muscle strength and structure is impacted by a pro-inflammatory cytokine called interferon-gamma, with and without exercise.

The team took these lab-grown muscles and inundated them with high levels of interferon-gamma for seven days. This experimental method was designed to mimic the effects of a long-lasting chronic inflammation.

As they expected, muscle tissue shrank and lost much of its strength over the course of a week.

Next, the team replicated this experiment — putting the muscle through a simulated exercise regime by stimulating the tissue using a pair of electrodes, on top of exposing the tissue to interferon-gamma.

Not only did the exercising muscle not waste away, it actually grew over the week-long period. Exercise had a profoundly protective effect, almost completely preventing the negative effects of chronic inflammation.

The team also found that simulated exercise inhibited a specific inflammatory molecular pathway in muscle cells. To prove that this signaling pathway is the "main culprit" of the observed inflammatory response, the team applied FDA-approved drugs that specifically block this pathway and observed similar protective effects to those of simulated exercise, Bursac explains.

The team tested this theory using two drugs called tofacitinib and baricitinib, which are used to treat rheumatoid arthritis and block the same inflammatory pathway as exercise.

WHY IT'S A HACK — Taken together, the results show that exercising muscles have an innate ability to counteract chronic inflammation in the body, preventing negative downstream effects like muscle atrophy and weakness.

When exercising, muscle cells were directly opposing the pro-inflammatory signal induced by interferon-gamma, Bursac explains.

"We are looking to further understand this muscle's 'self-defense' mechanism including if it happens directly inside muscle cells or if muscle cells secrete out some factors, which then act back on muscle," Bursac says. "By uncovering specific molecular mechanisms, we hope to eventually identify novel anti-inflammatory targets for potential pharmacotherapy."

Interestingly, these findings take on particular salience in light of Covid-19. That's because, when the body fights Covid-19, the immune system can spiral out of control, causing an inflammatory "overreaction" called a cytokine storm.

Some of the same inflammatory signaling pathways found to be countered by muscle exercise are the pathways that are upregulated in Covid-19 related "cytokine storms".

Exercise may modulate the severity of Covid-19 via inflammation, too. In a recent study published by the Mayo Clinic, researchers found that people who have a higher maximum exercise capacity (those who can exercise longer and harder than others) have lower chances of being hospitalized due to Covid-19.

Furthermore, the very same drugs tested in the study that suppressed muscle inflammation via the same pathway as exercise have been used in clinics to suppress the inflammatory response in Covid-19, Bursac adds.

"This indeed would imply that at least some forms and intensities of exercise would be beneficial against the excessive inflammatory response in Covid-19," Bursac says.

However, not everyone may benefit because some people have conditions that make exercise difficult. This is unfortunately true for chronic inflammation as well; its side-effects include chronic fatigue, body pain, and depression — all hurdles to exercise.

SCIENCE IN ACTION — The study was conducted using lab-grown muscle tissue, not human subjects. Therefore, the results don't point to a specific "anti-inflammation workout."

The exercise regime applied to lab-grown muscles was one hour every eight hours for seven days, which is "too intense to be applied in real life," Bursac says.

However, Bursac does suggest that everyday people should understand that regular exercise is beneficial for combatting inflammation.

"We are interested to find out if specific regimes of exercise, such as those mimicking resistance versus endurance training are particularly beneficial as an anti-inflammatory defense," Bursac says.

Future studies on various types of exercise may illuminate a routine that maximizes the anti-inflammatory benefits.

For now, the World Health Organization recommends doing at least 150 to 300 minutes of moderate-intensity aerobic physical activity or 75 to 150 minutes of vigorous-intensity aerobic physical activity a week. People should also lift weights or do resistance exercise two or more days a week.

Other actions like getting extra sleep, tamping down stress, and eating nutrient-rich, minimally processed food will also keep inflammation from running wild in the body.

HACK SCORE OUT OF 10 —🏋🏽‍♀️⛹🏻‍♂️🏄‍♂️🏊🏾🧘‍♀️🚴🏽‍♀️🤸‍♀️- Staying active and stress-free helps stave off excessive inflammation.

Abstract: Chronic inflammatory diseases often lead to muscle wasting and contractile deficit. While exercise can have anti-inflammatory effects, the underlying mechanisms remain unclear. Here, we used an in vitro tissue-engineered model of human skeletal muscle (“myobundle”) to study effects of exercise-mimetic electrical stimulation (E-stim) on interferon-γ (IFN-γ)–induced muscle weakness. Chronic IFN-γ treatment of myobundles derived from multiple donors induced myofiber atrophy and contractile loss. E-stim altered the myobundle secretome, induced myofiber hypertrophy, and attenuated the IFN-γ–induced myobundle wasting and weakness, in part by down-regulating JAK (Janus kinase)/STAT1 (signal transducer and activator of transcription 1) signaling pathway amplified by IFN-γ. JAK/STAT inhibitors fully prevented IFN-γ–induced myopathy, confirming the critical roles of STAT1 activation in proinflammatory action of IFN-γ. Our results reveal a previously unknown mechanism of the cell-autonomous anti-inflammatory effects of muscle exercise and establish the utility of human myobundle platform for studies of inflammatory muscle disease and therapy.