Study details

For the study, researchers looked at 25 people with long COVID and compared them to healthy people who had fully recovered from COVID-19 but didn't have any persisting symptoms.

Both groups of participants were asked to work out for around 10-15 minutes on a stationary bike until they gradually reached their maximum aerobic capacity. Researchers then took multiple blood draws and collected two muscle biopsies from the participants' thighs a week before they exercised and a day after.

The researchers found clear signs that mitochondria in the long COVID participants were compromised, and the muscle tissue was starved for energy. "We saw this immediately and it's very profound," said Braeden Charlton, one of the study's authors from Vrije University in Amsterdam.

Specifically, the researchers found that metabolites in the blood that are related to energy production were significantly lower in long COVID patients. These patients also started producing lactate, a "last resort" fuel for cells, much sooner during exercise than healthier patients, suggesting their cellular energy system was off, Stone reports.

"The mitochondria are operating at a severely reduced capacity compared to healthy people," Charlton said.

The researchers also found that long COVID patients ended up "having a lot more muscle damage than a healthy person would have," Charlton said. "And because their maximal capacity is now also lower, they have that damage happening at a sooner point."

The muscle tissue samples from long COVID patients showed more atrophy than the healthy patients, as well as "immense amounts" of cell death, which happens when immune cells infiltrate and degrade tissue, Charlton said.

This suggests there is some sort of altered immune response to exercise causing symptoms of exhaustion. "It's not just the functionality of their muscles, but the way that their immune system is receiving that exercise signal," Charlton said.

The muscle tissue samples also showed long COVID patients had an accumulation of microclots, which got worse following exercise.

Other research from South Africa found microclots in long COVID patients carry "trapped inflammatory molecules" indicating the patients' compromised vasculature. However, in the new study, there wasn't any evidence microclots were blocking tiny blood vessels but were instead lodged in the tissue.

Discussion

David Systrom, a physician at Harvard Medical School and Brigham and Women's Hospital, said the study supports the idea that mitochondrial dysfunction plays a role in some long COVID symptoms, like fatigue and post-exertional malaise.

"They were able to link symptoms to these organic changes," he said. "I was very impressed by that."

Meanwhile, Akiko Iwasaki, a professor of immunology at Yale University, said the tissue-level analysis of defects in the muscle was "striking" and could help explain the pain, fatigue, and weakness long COVID patients experience.

Iwasaki especially noted the finding that T cells from the immune system infiltrated the muscles of long COVID patients, which could indicate "an autoimmune response within the muscle cells."

"In the healthy muscle, they find very few, if any T cells," she added.

Resia Pretorius, a professor of physiological sciences at Stellenbosch University in South Africa said the implications of the study's findings about microclots could be huge.

"That means the microclots can actually have traveled through the damaged vasculature into the muscle," she said. "What is scary, but possibly very significant, is that this might be happening in other tissues as well."

If that's the case, the microclots could reflect how damaged the blood vessels' lining is are, which could potentially impair the delivery of oxygen to the muscle tissue.

If the vasculature is "totally shot," the "mitochondria will be massively affected," Pretorius said, adding that more work needs to be done before drawing any definitive conclusions.

Should long COVID patients exercise to treat post-exertional malaise?

Whether exercise helps with post-exertional malaise is still "intensely controversial," Systrom said.

"Post-exertional malaise is a unique symptom in these disorders and is not a feature of deconditioning," he said. "You cannot simply ask these patients to go to the gym and fix the problem."

Systrom noted it's possible some long COVID patients could benefit from gradual exercise, especially after first establishing some successful medical treatment.

David Putrino, director of rehabilitation innovation at Mount Sinai Health System, said he believes the study is a wake-up call for the medical field, showing clear evidence for the energy crash and symptoms long COVID patients and others with similar conditions experience.

"As opposed to what's been sold to patients over the last few decades, that symptoms such as extreme fatigue and exertional malaise are psychological or physical conditioning issues," he said. "Physical exertion does harm to the bodies of people with these illnesses."

Generally, Putrino recommends avoiding exercise if you have post-exertional malaise and instead practice "energy conservation."

Putrino prescribes "autonomic rehabilitation" to patients at his clinic, a type of rehabilitation that's done at a much lower intensity and duration, taking post-exertional malaise into account.

"We need to step out of this erroneous mindset of no pain, no gain," he said. (Stone, "Shots," NPR, 1/9)

Read our overview of COVID-19 recovery clinic models pioneered by early adopters, and considerations for assessing whether it is a model you should pursue.