A series of new studies has uncovered important insights into why many patients with long COVID experience profound fatigue and other symptoms when they try to exercise. The research points to specific abnormalities in skeletal muscle structure and energy production that help explain the crippling muscle pain, exhaustion, and “brain fog” that can persist for months or years after a COVID-19 infection.
Muscle Biopsies Reveal Structural Changes
In a study published this week in the journal Nature Immunology, researchers performed muscle biopsies on long COVID patients and found damage to the energy-generating parts of muscle cells called mitochondria. Patients in the study experienced severe fatigue and other symptoms with even minor exertion.
Using electron microscopy imaging, the team observed extensive disruptions to the internal structure of patient muscle cell mitochondria compared to healthy volunteers. These abnormalities likely prevent muscles from producing adequate energy during activity, resulting in rapid exhaustion and malaise.
“Our findings indicate that in some long COVID patients, there is impaired energy generation inside muscle cells, which explains their profound and persistent fatigue,” said senior author Dr. Michael Sneller. By clearly identifying muscle mitochondria injuries, the study provides an explanation for post-exertional malaise that plagues over half of long COVID sufferers.
Mitochondrial Dysfunction Limits Energy Supply
In healthy people, mitochondria produce 90% of the chemical energy that powers muscle contraction. Physical exertion places high demands on these tiny organelles to supply extra energy on demand.
Long COVID wreaks havoc on this finely-tuned system. When patients attempt to exercise, their damaged mitochondria cannot increase energy production to meet these spiking needs. Muscles quickly become exhausted, pain and cognitive dysfunction set in, and full recovery takes far longer than normal.
“It’s like driving a car that has transmission problems and lacks the power to go up a steep hill,” explained study co-author Dr. Peter Chin-Hong. “Any amount of exertion makes the engine stall out.”
This research confirms what patients have reported experiencing for almost three years since initially falling ill with COVID-19. Simple tasks like climbing stairs or going for a short walk trigger disabling fatigue, muscle weakness, headaches, “brain fog”, nausea, racing heartbeat, and more – symptoms that can last for days or weeks after activity.
Known as “post-exertional malaise”, this prolonged exhaustion and sickness following physical or mental exertion is a hallmark symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and other post-viral illnesses. Researchers now have evidence it stems from defective muscle cell energy metabolism.
Patients Show Signs of Prior Viral Infection
In a separate study published this month in the journal Cell, researchers found remnants of SARS-CoV-2 virus inside muscle cells of some long COVID patients. The team also observed high levels of antiviral T cells concentrated near damaged mitochondria.
“The findings suggest that in some patients, mini-reservoirs of virus persist in muscle tissue long after the initial infection,” said co-lead author Dr. Jennifer Su. “This may spark ongoing inflammation and mitochondrial injuries.”
By providing evidence that long COVID is associated with viral persistence and muscle-localized autoimmunity, the study indicates post-viral inflammatory processes likely contribute to mitochondrial impairments underlying post-exertional malaise.
“We now have clear evidence linking long COVID to both past viral infection and an immune response that refuses to dissipate,” said senior author Dr. Akiko Iwasaki. “This gives us targets to focus treatments to potentially ease patient suffering.”
Abnormal Immune Activation Triggers Mitochondrial Problems
Additional new research found that long COVID patients exhibit chronic activation of certain immune cells and proteins that can damage muscle cell mitochondria.
“We identified blood biomarkers of pathways associated with metabolically impaired mitochondria in skeletal muscle,” said lead author Dr. Michael Peluso. “This reveals how viral infection, inflammation, and bioenergetic insufficiency are tied together in long COVID patients.”
The study measured abnormal behavior of natural killer cells and elevated levels of leukotrienes – immune proteins that can attack mitochondria – in the blood of long COVID patients vs healthy controls. These molecular indicators of immune dysfunction were most pronounced in patients with the most severe fatigue and exertional intolerance.
“Immune activation alone can damage mitochondrial function without the virus necessarily still being present,” noted Dr. Lucinda Bateman, founder of the Bateman Horne Center, which treats ME/CFS and chronic fatigue. These new findings “help explain how inflammation drives mitochondrial energy deficiency seen in post-viral illness,” she said.
By uncovering these connections, scientists are building an understanding of the complex, self-reinforcing web of damage linking viral persistence in tissues, chronic inflammation, autoimmunity, and cellular metabolism problems in long COVID. Therapies targeting each of these areas may need to be combined to fully address the disease’s protean symptoms.
Exercise Guidance for Long COVID Patients
For long haulers planning to exercise through their illness, extreme caution is warranted based on these revelations regarding what activity can trigger.
“Until we better understand the full duration and pathologic consequences of immune activation in long COVID, patients recovering from COVID-19 should take a very gradual approach to exercise,” advised Dr. Amy Kontor, cardiologist at Mount Sinai.
The Centers for Disease Control (CDC) recommends long COVID patients start with 5-10 minutes of gentle activity at an intensity that feels “very, very easy” to avoid post-exertional relapse. Increments of no more than 10% should be added week-to-week based on tolerance. Heart rate, blood pressure, oxygen saturation, and symptoms must be closely monitored the entire time.
Most importantly, long haulers should listen carefully to the limits of their own body rather than push through discomfort, experts emphasize. Trying to exercise one’s way out of long COVID could instead provoke serious mitochondrial crashes linked to disease progression.
“Symptoms are signals from your body about the state of recovery and current capacity,” explained Dr. Alison Bested, author of Recovery from Chronic Fatigue Syndrome. “We now know depletion of cellular energy likely causes exercise intolerance in this disease. Respecting your body’s signals is vital.”
Ongoing Research Critical
Much more research across scientific disciplines is urgently needed to further clarify the complex biology of post-exertional malaise in long COVID in order to identify treatments and preventions.
“Continued federal investment into cross-discipline basic science collaborations is critical to advance our mechanistic understanding of the disease so we can help the millions suffering,” said Dr. Avindra Nath, intramural clinical director at the National Institute of Neurological Disorders and Stroke.
The scientific community owes a huge debt of gratitude towards long COVID patient advocates who helped accelerate biomedical research through staunch advocacy when the disease was initially dismissed as psychosomatic. Their early calls for funding investigative muscle biopsies provided the foundation of evidence enabling recent revelations.
“Patients showed us where to look first,” acknowledged Dr. Yamamoto. “We are hopeful our discoveries can now be translated into therapies to ease their very real suffering.”
For long haulers coping through each day, every step towards answers in understanding post-viral illness mechanics represents hope on the long road to recovery.
Summary of Key Points
|Structural damage to muscle cell mitochondria
|Reduced capacity to produce energy needed for exercise
|Persistence of viral remnants in muscle tissue
|Ongoing immune attack damages mitochondria
|Chronic immune system activation
|Leukotrienes & other factors impair mitochondrial function
|Post-exertional malaise a defining symptom
|Clear sign of energy deficiency within muscle cells
|Extreme caution needed around exercise
|Too much can trigger crushing relapses
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