Long COVID continues to impact millions globally, with a myriad of lingering symptoms that can persist for months or even years after the initial COVID-19 infection. One of the most common and debilitating symptoms is a substantially reduced ability to exercise and perform physical activities without triggering a severe worsening of fatigue, muscle pain, breathlessness, and other symptoms – a condition known as post-exertional malaise (PEM).
Now, groundbreaking research published this week in Nature Immunology has uncovered the underlying biological mechanism that drives this exercise intolerance in long COVID patients. Using sophisticated analysis of muscle biopsies in long COVID patients, the study found strong evidence that the mitochondria (the “power plants” that generate energy inside cells) of skeletal muscle tissue are extensively damaged by the initial COVID-19 infection. This damage then reduces the muscles’ ability to respond to increases in energy demand – such as occurs during exercise.
Mitochondrial Dysfunction At The Root of Post-Exertional Malaise
When long COVID patients attempted even mild-to-moderate exercise, their damaged muscle mitochondria were unable to ramp up energy production to meet the heightened demand. This forces the skeletal muscle tissue to suddenly switch to less efficient anaerobic metabolic pathways to maintain energy supply, triggering a cascade of inflammatory signals and symptoms like fatigue, pain, and shortness of breath.
“Our findings suggest long COVID patients’ debilitating post-exertional symptoms are driven by damaged mitochondria that struggle to generate sufficient energy during physical activity,” said senior study author Dr. Amy Lam of the Gladstone Institutes. “This starves the muscles of energy, causing patients to ‘hit the wall’ much sooner than expected when exercising.”
This breakthrough adds crucial evidence to the leading theory that long COVID arises from viral reservoirs persisting in body tissues long after the initial infection has cleared. In this case, remnants of SARS-CoV-2 virus remain inside muscle tissues, where they inflict ongoing damage to mitochondria.
Viral Persistence Drives Mitochondrial Impairment Over Time
Other recent research has also found traces of SARS-CoV-2 genetic material and proteins inside various organs and tissues, months or longer after a patient has recovered from the acute infection phase. This includes heart muscle, the lungs, the brain, and elsewhere.
“The latest data clearly links long COVID symptoms to the after-effects of viral persistence and replication in tissues like muscle, despite the infection being cleared from the respiratory system,” said infectious disease expert Dr. Monica Gandhi of UCSF, who was not involved in the study.
In muscle tissues specifically, the Gladstone team found that longer duration of long COVID symptoms correlated with increasing mitochondrial damage and more severe post-exertional malaise. This aligns with the hypothesis that viral remnants continue eroding mitochondrial function over time.
Gradual Recovery Possible, But Exercise Caution Advised
Importantly, the study also showed some long COVID patients do eventually regain more normal mitochondrial function and exercise ability – but this process can take 12 months or longer. Younger patients also tended to recover faster.
“We did observe gradual recovery of mitochondrial activity over time in a subset of participants,” said Dr. Lam. “But persistent mitochondrial dysfunction lasting a year or more was linked to more severe long COVID outcomes.”
Consequently, extreme caution with physical over-exertion is warranted for all long COVID patients. There is a risk that overly strenuous exercise while muscle mitochondria remain damaged could trigger PEM relapses and further long-term harm.
“Based on these game-changing revelations on long COVID mitochondrial damage, post-COVID exercise advice must be updated to reflect the increased risks,” said sports medicine specialist Dr. Leila Mirza of The Ohio State University. “While light activity can be beneficial, patients with ongoing fatigue or post-exertional malaise should avoid intensive training and consult a doctor.”
Ongoing Research Critical To Uncover Full Scope of Long COVID Impacts
Experts say the growing body of long COVID research underscores the importance of ongoing investigation even two years into the pandemic. Critical knowledge gaps remain on the full spectrum severity and duration of long COVID outcomes.
“Long COVID is an enormously complex, multi-faceted condition. We are still identifying new manifestations and diagnoses months or longer after initial infection,” said Dr. Gandhi.
“The muscle mitochondrial damage now evident could also be occurring in other tissues we haven’t examined yet. And there may be multiple different pathways leading to the post-COVID conditions grouped under ‘long COVID’. Much more research across the spectrum is urgently needed.”
In addition to investigating disease mechanisms, experts stress the need to advance diagnostics that can readily identify long COVID patients at high risk of severe long-term outcomes. There is also an urgent need to develop treatments that can effectively resolve symptoms by addressing root causes like persistent infection reservoirs and mitochondrial dysfunction.
Several clinical trials are underway evaluating antiviral therapies and other treatments targeting hypothesized long COVID disease mechanisms. For now, basic prevention via COVID-19 vaccination and boosters remains the best way to reduce risks of any long-term impacts. However, breakthrough infections in vaccinated individuals show that long COVID can still occur.
Mitochondrial Biomarkers Could Enable Improved Long COVID Diagnostics
Based on these new mechanistic insights into long COVID pathology, the Gladstone research team suggests assays detecting mitochondrial damage may have value as diagnostic biomarkers.
“Measuring mitochondrial dysfunction in muscle or other tissues could be a game-changer for identifying patients at high risk of severe long COVID outcomes” said Dr. Lam.
Standardizing assays for biomarkers of mitochondrial damage and metabolic dysfunction would enable early identification of high-risk long COVID cases. This could ensure appropriate lifestyle adjustments and treatment interventions are implemented quickly to stabilize outcomes and support recovery.
Ongoing research in this area is urgent and essential, as the long COVID patient population continues growing. Clear guidance will be vital on safe levels of physical activity, advice on pacing/energy envelope management, and customized rehab protocols that promote recovery not relapse.
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