Exercise Energizes Patients With Autoimmune Disease

IRP Study Points to the Biological Roots of Physical Activity’s Benefits

By Brandon Levy

Tuesday, February 7, 2023

British science fiction writer Arthur C. Clarke once wrote that, “Any sufficiently advanced technology is indistinguishable from magic.” While not exactly a “technology,” exercise has such wide-ranging health benefits that it could understandably be mistaken for magic. Still, scientists persist in investigating precisely why physical activity is so good for us. Recently, a small IRP study showed that exercise training can help reduce the debilitating fatigue that often accompanies the autoimmune disease known as lupus, and also illuminated some of the underlying mechanisms that may lead to those benefits.¹

Like other autoimmune diseases, lupus occurs when a person’s own immune system attacks his or her body. This immune assault causes a variety of symptoms, including fatigue so severe that it prevents patients from pursuing activities that healthy people can do without a second thought.

“Fatigue is a major concern and quality of life issue for patients with lupus,” says IRP staff clinician Sarfaraz Hasni, M.D., the new study’s first author. “It’s an overwhelming feeling of fatigue to the extent that they’re not able to do normal activities of daily living. It’s a topic of great research interest because nobody understands what causes this extreme amount of fatigue not just in lupus but also in other autoimmune diseases.”

“It’s a feedback loop,” adds IRP staff scientist Lisa Chin, Ph.D., the study’s senior author. “You don’t do much activity because you don’t feel good, and that leads to further deconditioning in an endless cycle of fatigue that’s hard to get out of.”

While numerous past studies showed that exercise can help break that cycle, the biological reasons why it does so remained largely unexplored. In the new study, an interdisciplinary group of researchers from across the IRP worked together to shed some light on how exercise affects lupus patients’ bodies, including their genes and the energy-generating mitochondria that power their cells.

As part of the study, 16 women with lupus came to the NIH Clinical Center three times per week for 12 weeks to do 30 minutes of intense treadmill walking. At the end of the study, patients reported that they were experiencing significantly less fatigue in their everyday lives than they had before, along with improved mental health and sleep.

However, the study did not rely solely on subjective self-reports that could be influenced by the placebo effect. The IRP team also measured changes in the participants’ ‘anaerobic threshold,’ which indicates when the body begins to rely on different energy sources during exercise. Initially, our cells keep us moving by using processes that require plenty of oxygen, but sustained, vigorous physical activity eventually causes them to switch over to ‘anaerobic’ methods that don’t need much oxygen. This change occurs near the point at which exercisers begin to feel worn out, and the study showed that 12 weeks of exercise training markedly lengthened the time it took for participants to reach the anaerobic threshold during a progressively more challenging exercise test.

“Think of it as an indication for when fatigue is imminent,” Dr. Chin explains. “If you can delay the time it takes to hit this anaerobic threshold, it means you’ve delayed fatigue.”

“Patients don’t know where this threshold is,” she continues. “It’s a very objective marker because it’s assessed after the exercise test and is not based on input from the patient.”

Interestingly, the IRP team found evidence suggesting that exercise reduces lupus patients’ fatigue in part by improving the energy output of their cells’ mitochondria. The more that a participant’s mitochondria ramped up energy production after the 12 weeks of exercise training, the greater that person’s reduction in fatigue symptoms tended to be.

Another potential reason that exercise reduced the participants’ fatigue may have been by decreasing the amount of a substance called interferon in their bodies. Interferon is known to be a major driver of lupus, but it is hard to measure its concentration in the blood. However, when its levels increase, it boosts the activity of a set of genes called interferon-stimulated genes (ISGs), so examining the behavior of those genes can provide a proxy measurement for interferon levels in the body. When the IRP researchers looked at how the activity of ISGs changed in their participants over the course of the study, they found that slightly more than half of the participants not only had increased mitochondrial energy output but also a marked reduction in the activity of their ISGs.

“If the ISGs are high at the beginning, it means there’s a lot of interferon driving the disease, and then later on if it goes down, it means the disease is possibly not as severe,” Dr. Hasni explains.

Dr. Hasni and Dr. Chin caution that because the IRP study was small, additional research will be needed to determine with more certainty the biological roots of exercise’s benefits for lupus patients. It also remains unclear what type and amount of exercise is required to produce those effects. Nevertheless, the IRP study provided important clues that scientists can pursue further to figure out the best ways to reduce fatigue in individuals with lupus. Those interventions could include exercise, a medication that boosts mitochondrial function, or — most likely — a combination of approaches.

“With exercise, it’s a systemic change that you’re making, so it’s hard to pinpoint exactly what it does, but this study points to mitochondrial dysfunction as contributing to the fatigue,” Dr. Chin says. “It’s definitely something to look more into with larger trials.”

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References:

[1] Hasni S, Feng LR, Chapman M, Gupta S, Ahmad A, Munday A, Mazhar MA, Li X, Lu S, Tsai ML, Gadina M, Davis M, Chu J, Manna Z, Nakabo S, Kaplan MJ, Saligan L, Keyser R, Chan L, Chin LMK. Changes in cardiorespiratory function and fatigue following 12 weeks of exercise training in women with systemic lupus erythematosus: a pilot study. Lupus Sci Med. 2022 Oct;9(1):e000778. doi: 10.1136/lupus-2022-000778.

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