Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated Evidence

Abstract

Background: Recent studies provide strong evidence for a key role of skeletal muscle pathophysiology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In a 2021 review article on the pathophysiology of ME/CFS, we postulated that hypoperfusion and ischemia can result in excessive sodium and calcium overload in skeletal muscles of ME/CFS patients to cause mitochondrial damage. Since then, experimental evidence has been provided that supports this concept.

Methods: We collect, summarize and discuss the current state of knowledge for the key role of skeletal muscle pathophysiology. We try to explain which risk factors and mechanisms are responsible for a subgroup of patients with post COVID syndrome (PCS) to develop ME/CFS (PC-ME/CFS).

Results: Mitochondrial dysfunction is a long-held assumption to explain cardinal symptoms of ME/CFS. However, mitochondrial dysfunction could not be convincingly shown in leukocytes. By contrast, recent studies provide strong evidence for mitochondrial dysfunction in skeletal muscle tissue in ME/CFS. An electron microscopy study could directly show damage of mitochondria in skeletal muscle of ME/CFS patients with a preferential subsarcolemmal localization but not in PCS. Another study shows signs of skeletal muscle damage and regeneration in biopsies taken one day after exercise in PC-ME/CFS. The simultaneous presence of necroses and signs of regeneration supports the concept of repeated damage. Other studies correlated diminished hand grip strength (HGS) with symptom severity and prognosis. A MRI study showed that intracellular sodium in muscles of ME/CFS patients is elevated and that levels correlate inversely with HGS. This finding corroborates our concept of sodium and consecutive calcium overload as cause of muscular and mitochondrial damage caused by enhanced proton-sodium exchange due to anaerobic metabolism and diminished activity of the sodium-potassium-ATPase. The histological investigations in ME/CFS exclude ischemia by microvascular obstruction, viral presence or immune myositis. The only known exercise-induced mechanism of damage left is sodium induced calcium overload. If ionic disturbance and mitochondrial dysfunction is severe enough the patient may be captured in a vicious circle. This energy deficit is the most likely cause of exertional intolerance and post exertional malaise and is further aggravated by exertion.

Conclusion: Based on this pathomechanism, future treatment approaches should focus on normalizing the cause of ionic disbalance. Current treatment strategies targeting hypoperfusion have the potential to improve the dysfunction of ion transporters.

Keywords: long COVID; mitochondrial damage; myalgic encephalomyelitis/chronic fatigue syndrome; post–COVID‐19; skeletal muscle; vascular dysfunction.

FIGURE 1

Several mechanisms triggered by an infection can result in circulatory disturbance and hypoperfusion of muscles including autoantibodies [41], inflammation [22], sympathetic overactivity [10], endothelial dysfunction [42], impaired red blood cell deformability [43] and diminished preload [10]. Upon exertion, hypoperfusion of skeletal muscles leads to rise in protons, intracellular sodium and calcium [12], muscle necrosis [9], mitochondrial damage and enhanced production of reactive oxygens [13, 22]. 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. ß2AdR: ß2‐adrenergic receptor; CGRP: calcitonin‐gene–related peptide; ROS: reactive oxygen species. Biorender was used to create the figure.

FIGURE 2

In PCS with fatigue and exertional intolerance, a predominant microvascular disturbance with inflammation was found early in disease [17, 25] which was no more evident later [9, 24]. While patients with PCS frequently improve in health during the 2nd year, those with PC‐ME/CFS stagnated at their initial level [8]. Risk factors for the development of ME/CFS are autoantibodies, collagen diseases like Ehlers–Danlos and joint hypermobility as well as genes regulating mitochondrial, vascular and muscle function [59, 60]. Mast cell hyperactivity and dysfunction of the ion channel TRPM3 may be the other risk factors [61, 62, 63].