Go to the gym. Get in shape.
That’s what many long COVID patients are told when they tell about the overwhelming fatigue that engulfs them even after mild physical activity.
These symptoms of burnout, or post-exertional malaise as it’s called, are hallmarks of long COVID and complex ailments like chronic fatigue syndrome, or ME/CFS.
The idea that exercise can help patients has proven difficult to shake — despite evidence suggesting this isn’t merely a case of deconditioning that patients can overcome by pushing through the pain.
“I don’t think the messaging has been strong enough,” says David Putrino, the director of rehabilitation innovation for Mount Sinai Health System. “It is very clear that this is not a typical response to exercise.”
A paper published this month in Nature Communications now adds new weight to this assessment.
By performing biopsies on long COVID patients before and after exercise, Dutch scientists have painted an unexpected picture of widespread abnormalities in muscle tissue that would possibly lead to this severe reaction to physical activity.
Among the most surprising findings are clear symptoms that mobile power plants, mitochondria, are compromised and tissues lack energy.
“We saw it and it’s very profound,” says Braeden Charlton, one of the study’s authors from Vrije University in Amsterdam.
Tissue samples from long COVID patients also exhibit severe muscle damage, an altered immune response, and a buildup of microclots.
“This is a very real disease,” says Charlton. “We see this at basically every parameter that we measure.”
Most people will get delayed onset muscle soreness after a tough workout, but post-exertional malaise is a different animal altogether.
“It’s not just a pain,” says Charlton. For a lot of people, it’s absolutely debilitating for days or even weeks. “
Although symptoms vary, the most common are muscle aches, increased fatigue, and cognitive problems, known as “brain fog,” that last up to a week after physical exertion.
The study, founded at the UMC Health Center in Vrije and Amsterdam, compared 25 other people with long COVID to healthy controls who had fully recovered from COVID-19 and had no lingering symptoms. Both teams were asked to train for about 10 to 15 minutes on a desk bike, until they reached their maximum aerobic capacity.
The researchers took several blood samples and two muscle biopsies from the thighs, a week before the workout and a day after.
“Their baseline was already impaired and that dropped even lower with the maximal exercise,” says Charlton.
As other extensive COVID studies show, the challenge isn’t similar to how their lungs or hearts work. Rather, anything that prevents the muscle from absorbing oxygen from the blood.
Using a technique called respirometry, the Dutch researchers oversupplied oxygen to the muscle tissue and found evidence the mitochondria weren’t functioning properly
Blood metabolites similar to energy production were also particularly reduced in long COVID patients. And they began generating lactate, a “last resort” fuel for cells, much earlier in training than healthy ones, but some other sign that their cellular energy formula had gone wrong.
“In healthy people, mitochondria have a particularly reduced capacity,” Charlton says.
Taken together, the findings give rise to speculation that mitochondrial disorder plays a role in long COVID symptoms, such as fatigue and post-exertional malaise, says Dr. David Systrom, a physician at Harvard Medical School. and Brigham and Women’s Hospital.
“They were able to associate the symptoms with those biological changes,” he explains. “I was inspired through that. “
In his own research, Systrom found evidence of abnormal oxygen intake through maximal skeletal muscle training in patients with long COVID and ME/CFS, indicating that there is a challenge with oxygen delivery to the mitochondria.
Meanwhile, the Dutch study suggests there could be “intrinsic dysfunction” of the mitochondria’s ability to produce energy, he says.
Systrom says it’s possible for either thing to happen in long-term COVID patients. “There would possibly be two ends of that spectrum,” he says. It’s actually something that long-term work will have to consider. “
The story doesn’t end with mitochondria, either.
Muscle biopsies performed after the strain revealed other concerning developments.
“They end up suffering a lot more muscle damage than a healthy user would,” Charlton says. “And because their maximum capacity is now also lower, that pain happens sooner. “
A close look at the muscle tissue showed that long COVID patients had more atrophy (shrinkage of fibers) than healthy controls. There have also been “immense amounts” of mobile death, or “necrosis,” when immune cells infiltrate and degrade. knitted, she says.
Knowledge recommends some impaired immune reactions to exercise in post-exertional discomfort.
“It’s just about the capacity of your muscles, but also how your immune formula gets that training signal,” Charlton says.
Studying muscle defects at the point of tissue is “amazing” and can alleviate the pain, fatigue and weakness patients experience, says Akiko Iwasaki, a professor of immunobiology at Yale University, who was not involved in the study.
The further discovery that T cells, a component of the immune system’s arsenal, had infiltrated the muscles of long COVID patients also caught Iwasaki’s attention, likely indicating “an autoimmune reaction within muscle cells. “
“In the healthy muscle, they find very few, if any T cells,” she says.
The deep dive into muscle tissue also revealed some other familiar trait in the long-running pathology of COVID: microclots.
The researchers found that those symptoms increased sharply in other people with symptoms, a feature that only worsened after exercise.
South African researchers analyze microclots involving “trapped inflammatory molecules” as an indication of a compromised vascular formula in patients.
In the Dutch study, there wasn’t evidence that microclots were blocking the tiny blood vessels, which was one hypothesis. Instead, they were lodged in the tissue.
The implications of this location are potentially huge, says Resia Pretorius, a professor of physiological sciences at Stellenbosch University in South Africa, who was not involved in the existing study.
“This means that the microclots would possibly have traveled through the broken vasculature to the muscle,” he says. “What’s frightening, though perhaps very significant, is that this can occur in other tissues as well. “
In this scenario, the microclots may simply reflect the extent of the damage to the blood vessel wall, which would also affect the supply of oxygen to muscle tissue.
If the vascular formula is “totally affected,” Pretorius says “mitochondria will be greatly affected,” more work needs to be done before corporate conclusions can be drawn.
The underlying reasons for long COVID remain elusive; However, a prevailing theory is that an ongoing chronic infection can have subsequent consequences.
The researchers tested this hypothesis. They found evidence of SARS-CoV-2 viral proteins in muscle tissue, but found no difference between long COVID organization and controls, leading them to conclude that these are viral remnants that are not necessarily part of the malaise. post-exertion.
The role of exercise in treating post-exertional discomfort remains “extremely controversial,” says Harvard’s Systrom, who has studied exercise in the context of complex chronic diseases such as ME/CFS.
“Post-exertional discomfort is a symptom unique to these disorders and is not a feature of deconditioning,” he says. “You can’t just ask those patients to go to the gym and fix the problem. “
Long COVID is itself a general term that covers a wide range of symptoms that may have other underlying causes.
Systrom says it’s conceivable that a subset of those patients would derive more benefits than others from progressive exercise, especially after effective medical treatment is initiated.
In their study, Charlton says they examined other studies to determine that what they observed came from physical inactivity. It also notes that the long COVID patients who signed up were bedridden and taking an average of 4,000 steps per day.
Mount Sinai’s Putrino sees the study as a much-needed wake-up call to the broader medical picture: clear evidence of a biological basis for the drop in energy and the onslaught of symptoms experienced by long COVID patients.
“Contrary to what has been sold to patients over the past few decades, symptoms such as excessive fatigue and discomfort from exertion are physical or mental fitness issues,” he says. “Physical exertion damages the bodies of other people with these diseases. “
Their general recommendation is to exercise if you suffer from post-exertional discomfort and practice “energy conservation” instead.
At his clinic, Putrino prescribes what’s called “autonomic rehabilitation” for these patients.
While the goal of training is to improve cardiovascular fitness (which might be proposed for patients recovering from severe pneumonia), this type of rehabilitation is carried out with a much lower intensity and duration and takes into account post-exertional discomfort.
“We want to get out of this mindset that there’s no pain and no gain,” he says.