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.