COVID-19 Causes Skeletal Muscle and Mitochondrial Damage That Contributes to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Medical News: A New Frontier in Understanding Post-Viral Conditions
The COVID-19 pandemic has left a legacy far beyond its acute phase, with millions of survivors experiencing lingering symptoms collectively termed Long COVID or Post-COVID Syndrome (PCS). Among these, a significant subset of individuals has been diagnosed with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). This debilitating condition, characterized by profound fatigue, cognitive impairment, and post-exertional malaise, has long eluded definitive explanations. However, a groundbreaking study by researchers from the Charité - Universitätsmedizin Berlin in Germany, Mitodicure GmbH in Kriftel, and the Goethe University Frankfurt am Main in Germany, sheds new light on the role of skeletal muscle and mitochondrial damage in the development of ME/CFS.

COVID-19 Causes Skeletal Muscle and Mitochondrial Damage That Contributes to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Several mechanisms triggered by an infection can result in circulatory disturbance and hypoperfusion of muscles including auto anti-bodies, inflammation, sympathetic overactivity, endothelial dysfunction, impaired red blood cell deformability and diminished preload. Upon exertion, hypoperfusion of skeletal muscles leads to rise in protons, intracellular sodium and calcium, muscle necrosis, mitochondrial damage and enhanced production of reactive oxygens. In ME/CFS, the activation of the sodium pump (Na+/K+ -ATPase) upon exertion may be diminished due to low ATP and dysfunctional ß2AdR and CGRP. At a certain level of intracellular sodium, the sodium-calcium-exchanger NCX changes its transport mode from calcium export to calcium import causing calcium overload that causes mitochondrial and myocyte damage. As a result, low ATP and ROS production further impair the sodium pump. ROS also impairs vascular function and perfusion. A vicious circle arises

This Medical News explores the mechanisms and findings of this pivotal research, which reveals how COVID-19-induced damage to skeletal muscles and their mitochondria may play a crucial role in perpetuating the symptoms of ME/CFS. By integrating histological, imaging, and biochemical insights, the study opens avenues for better diagnosis and therapeutic strategies.
 
The Pathophysiology Unveiled: Muscle Damage and Mitochondrial Dysfunction
Long suspected to underlie the hallmark symptoms of ME/CFS, mitochondrial dysfunction has now been directly observed in skeletal muscle biopsies. Researchers have shown that COVID-19-related hypoperfusion - a condition where tissues receive inadequate blood flow - sets off a cascade of events leading to sodium and calcium overload in muscle cells. This ionic imbalance damages mitochondria, the cell’s energy powerhouses, resulting in energy deficits that contribute to exercise intolerance and post-exertional malaise.
 
Histological studies have revealed telltale signs of muscle pathology, including necrosis (tissue death), regeneration, and atrophy. One study, involving biopsies taken o ne day after exercise, demonstrated an increased presence of damaged and regenerating muscle fibers, supporting the concept of recurrent injury. The authors found that these injuries were not due to ischemia (a lack of blood supply), inflammation, or direct viral invasion, but rather a result of ionic disturbances triggered by metabolic stress.
 
MRI imaging added another layer of evidence, showing elevated sodium levels in the skeletal muscles of ME/CFS patients. This corroborates findings that prolonged anaerobic metabolism - a hallmark of energy-deprived cells - disrupts the sodium-potassium balance, further impairing mitochondrial function. These insights collectively point to a vicious cycle where mitochondrial dysfunction exacerbates cellular energy shortages, creating a feedback loop of worsening muscle damage.
 
Distinctive Findings in ME/CFS and Post-COVID Syndrome
One intriguing aspect of the study was its comparison of skeletal muscle pathology in PCS patients with and without ME/CFS. Electron microscopy revealed significant mitochondrial damage in the subsarcolemmal region (just beneath the cell membrane) of ME/CFS patients, a pattern not observed in non-ME/CFS PCS cases. This localization underscores the proximity of mitochondria to damaging ionic fluxes in these patients.
 
Interestingly, while early stages of PCS showed evidence of microvascular dysfunction - such as endothelial inflammation and microclots - these were absent in later stages or in those with ME/CFS. This suggests a transition from vascular-related pathologies to a predominantly mitochondrial dysfunction-driven condition. The study hypothesizes that the initial vascular disturbances may set the stage for persistent mitochondrial damage, especially in individuals with predisposing factors such as genetic susceptibilities or autoimmunity.
 
The Role of Ionic Imbalances and Calcium Overload
At the core of the observed pathology lies an imbalance in ion transport mechanisms. Hypoperfusion during physical exertion forces muscles to rely on anaerobic metabolism, leading to the overproduction of protons. These protons are expelled via sodium-proton exchangers, resulting in a rise in intracellular sodium levels. When ATP-dependent sodium-potassium pumps fail to correct this imbalance due to energy deficits, sodium overload triggers the reversal of calcium-sodium exchangers, causing calcium to flood the mitochondria.
 
Calcium overload is toxic to mitochondria, disrupting their structure and function. The damaged mitochondria further impair cellular energy production and increase reactive oxygen species (ROS) generation, creating oxidative stress that perpetuates the cycle of injury. Histological evidence from muscle biopsies supports this mechanism, showing necrotic fibers alongside regenerating ones - a sign of repeated damage and repair attempts.
 
Clinical Implications: From Biomarkers to Treatments
The study’s findings have significant implications for both diagnosis and treatment. Diminished handgrip strength, a simple and non-invasive measure, has emerged as a reliable biomarker correlating with symptom severity in ME/CFS. Similarly, MRI studies of intracellular sodium levels may offer diagnostic insights into the severity of mitochondrial dysfunction.
 
On the therapeutic front, the research underscores the potential of targeting vascular and mitochondrial pathways. Enhancing perfusion through vasodilators, improving mitochondrial function with metabolic supplements, and addressing autoimmunity through immunomodulatory therapies are promising directions. For example, the use of guanylate cyclase activators to improve microvascular flow and ATP production, or immunoadsorption techniques to remove pathogenic autoantibodies, may offer relief to patients trapped in the cycle of energy deficits and muscle damage.
 
A Broader Perspective: Why Some Patients Develop ME/CFS
Not all PCS patients progress to ME/CFS, raising questions about susceptibility factors. The study identifies several potential contributors, including genetic predispositions affecting mitochondrial and vascular functions, connective tissue disorders like Ehlers-Danlos syndrome, and autoimmunity. Autoantibodies targeting vasoregulatory receptors have been detected in ME/CFS patients, correlating with symptom severity. These findings suggest that a combination of genetic and environmental factors determines the transition from PCS to chronic ME/CFS.
 
Conclusion: Breaking the Cycle of Damage
The study’s revelations about the role of skeletal muscle and mitochondrial damage in ME/CFS mark a significant leap forward in understanding this enigmatic condition. By pinpointing the mechanisms behind energy deficits, the research provides a clearer roadmap for developing targeted therapies.

Addressing mitochondrial dysfunction at its root - by correcting ionic imbalances, enhancing blood flow, and neutralizing damaging autoantibodies - holds the promise of not only managing symptoms but potentially reversing the disease’s progression. However, translating these findings into effective treatments will require robust clinical trials and sustained research funding.
 
The findings were published in the peer-reviewed Journal of Cachexia, Sarcopenia and Muscle.
https://onlinelibrary.wiley.com/doi/10.1002/jcsm.13669
 
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