Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract

Chronic Fatigue Syndrome or Myalgic Encephaloymelitis (ME/CFS) is a frequent debilitating disease with an enigmatic etiology. The finding of autoantibodies against ß2-adrenergic receptors (ß2AdR) prompted us to hypothesize that ß2AdR dysfunction is of critical importance in the pathophysiology of ME/CFS. Our hypothesis published previously considers ME/CFS as a disease caused by a dysfunctional autonomic nervous system (ANS) system: sympathetic overactivity in the presence of vascular dysregulation by ß2AdR dysfunction causes predominance of vasoconstrictor influences in brain and skeletal muscles, which in the latter is opposed by the metabolically stimulated release of endogenous vasodilators (functional sympatholysis). An enigmatic bioenergetic disturbance in skeletal muscle strongly contributes to this release. Excessive generation of these vasodilators with algesic properties and spillover into the systemic circulation could explain hypovolemia, suppression of renin (paradoxon) and the enigmatic symptoms. In this hypothesis paper the mechanisms underlying the energetic disturbance in muscles will be explained and merged with the first hypothesis. The key information is that ß2AdR also stimulates the Na+/K+-ATPase in skeletal muscles. Appropriate muscular perfusion as well as function of the Na+/K+-ATPase determine muscle fatigability. We presume that dysfunction of the ß2AdR also leads to an insufficient stimulation of the Na+/K+-ATPase causing sodium overload which reverses the transport direction of the sodium-calcium exchanger (NCX) to import calcium instead of exporting it as is also known from the ischemia–reperfusion paradigm. The ensuing calcium overload affects the mitochondria, cytoplasmatic metabolism and the endothelium which further worsens the energetic situation (vicious circle) to explain postexertional malaise, exercise intolerance and chronification. Reduced Na+/K+-ATPase activity is not the only cause for cellular sodium loading. In poor energetic situations increased proton production raises intracellular sodium via sodium-proton-exchanger subtype-1 (NHE1), the most important proton-extruder in skeletal muscle. Finally, sodium overload is due to diminished sodium outward transport and enhanced cellular sodium loading. As soon as this disturbance would have occurred in a severe manner the threshold for re-induction would be strongly lowered, mainly due to an upregulated NHE1, so that it could repeat at low levels of exercise, even by activities of everyday life, re-inducing mitochondrial, metabolic and vascular dysfunction to perpetuate the disease.

An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

“…In a second paper we tried to explain the potential causes of the energetic disturbances in skeletal muscle, where again, dysfunctional ß2AdR could play a key role via the need for ß2AdR-mediated stimulation of the Na + /K + -ATPase during exercise, which is a critical transport system for skeletal muscle metabolism [ 40 ].…”

“…The aim of the present hypothesis paper is to propose causes of the frequent neurological symptoms in ME/CFS, and how the previously identified pathomechanisms could also translate into the neurological symptoms, that we have not addressed so far. In our unifying hypothesis of the pathophysiology of ME/CFS and the pathophysiology of the skeletal muscle disturbances [ 39 , 40 ] there is no need to assume a specific neurological pathology to explain the neurological symptoms. These are sufficiently explained by a stringent application of the ideas on the pathomechanisms already put forward in our previous two hypothesis papers.…”

Autonomic dysfunction in SARS-COV-2 infection acute and long-term implications COVID-19 editor’s page series

“…Myalgic encephalomyelitis (CME) or chronic fatigue syndrome is characterized by impaired stamina and post-exercise exhaustion. Because antibodies against β 2 adrenergic receptors have been reported in ME, autonomic dysfunction with vasoconstriction of blood vessels to the brain and exercising muscles and concomitant metabolically stimulated release of endogenous vasodilators causing suppression of renin and hypovolemia could represent a unifying pathophysiological process (reviewed in Wirth) [ 48 ]. Chronic fatigue is a common feature of PASC.…”

Broken Connections: The Evidence for Neuroglial Failure in ME/CFS

“…One of the undisputed pathological features in ME/CFS is mitochondrial dysfunction, sometimes explained as an isolated dysfunction of certain mitochondrial processes or explained in the context of a general cellular dysfunction. 306 As of now, however, it is unclear if the mitochondriopathy seen in ME/CFS is of a specific kind or origin and how this feature may tie into the overall pathological matrix of the disease. After all, mitochondrial dysfunction is seen in a wide range of diseases including autoimmune disorders like MS, in neurodegenerative diseases as well as in cardiovascular disorders.…”

“…Indeed, in the absence of evidence for a primary mitochondrial defect, the mitochondrial involvement observed in ME/CFS may reflect several upstream pathophysiological processes, especially inflammatory stimulation (from whatever source), generally restricted perfusion ("misery perfusion") or, more specifically, beta-2-dysfunction (the latter has been shown to contribute to mitochondrial dysfunction). 306,307 There is a lot of support for the notion that inflammatory stimulation may go along with or even induce mitochondrial dysfunction. Mitochondrial dysfunction and inflammatory processes have been shown to be closely interlinked.…”