Wirth Klaus J, Scheibenbogen Carmen
KOSA Pharma GmbH, Frankfurt am Main, Germany.
Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
J Transl Med. 2021 Apr 21;19(1):162. doi: 10.1186/s12967-021-02833-2.
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.
慢性疲劳综合征或肌痛性脑脊髓炎（ME/CFS）是一种常见的使人衰弱的疾病，病因不明。针对β2-肾上腺素能受体（β2AdR）的自身抗体的发现促使我们提出假说，即β2AdR功能障碍在ME/CFS的病理生理学中至关重要。我们之前发表的假说认为ME/CFS是一种由自主神经系统（ANS）功能失调引起的疾病：在β2AdR功能障碍导致血管调节异常的情况下，交感神经活动过度会导致脑血管收缩和骨骼肌血管收缩占优势，而在骨骼肌中，内源性血管舒张剂的代谢性刺激释放（功能性交感神经溶解）会对此起到对抗作用。骨骼肌中一种不明原因的生物能量紊乱在很大程度上促成了这种释放。这些具有致痛特性的血管舒张剂过度生成并溢出到体循环中，可以解释血容量不足、肾素抑制（矛盾现象）和不明原因的症状。在这篇假说论文中，将解释肌肉能量紊乱的潜在机制，并与第一个假说相结合。关键信息是，β2AdR还能刺激骨骼肌中的钠钾ATP酶。适当的肌肉灌注以及钠钾ATP酶的功能决定了肌肉的易疲劳性。我们推测，β2AdR功能障碍还会导致钠钾ATP酶刺激不足，从而引起钠超载，这会使钠钙交换体（NCX）的转运方向逆转，使其从输出钙变为输入钙，这在缺血再灌注模型中也是已知的。由此产生的钙超载会影响线粒体、细胞质代谢和内皮，进一步恶化能量状况（恶性循环），从而解释运动后不适、运动不耐受和疾病慢性化的原因。钠钾ATP酶活性降低并不是细胞内钠负荷增加的唯一原因。在能量状况不佳时，质子产生增加会通过钠质子交换体亚型1（NHE1）使细胞内钠升高，NHE1是骨骼肌中最重要的质子排出器。最后，钠超载是由于钠向外转运减少和细胞内钠负荷增加所致。一旦这种紊乱严重发生，再次诱发的阈值就会大大降低，主要是由于NHE1上调，以至于即使在低水平运动时，甚至在日常生活活动中也可能再次发生，从而再次诱发线粒体、代谢和血管功能障碍，使疾病持续存在。
