PDF(Pubmed)
Abstract：
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by various disabling symptoms including exercise intolerance and is diagnosed in the absence of a specific cause, making its clinical management challenging. A better understanding of the molecular mechanism underlying this apparent bioenergetic deficiency state may reveal insights for developing targeted treatment strategies. We report that overexpression of Wiskott-Aldrich Syndrome Protein Family Member 3 (WASF3), here identified in a 38-y-old woman suffering from long-standing fatigue and exercise intolerance, can disrupt mitochondrial respiratory supercomplex formation and is associated with endoplasmic reticulum (ER) stress. Increased expression of WASF3 in transgenic mice markedly decreased their treadmill running capacity with concomitantly impaired respiratory supercomplex assembly and reduced complex IV levels in skeletal muscle mitochondria. WASF3 induction by ER stress using endotoxin, well known to be associated with fatigue in humans, also decreased skeletal muscle complex IV levels in mice, while decreasing WASF3 levels by pharmacologic inhibition of ER stress improved mitochondrial function in the cells of the patient with chronic fatigue. Expanding on our findings, skeletal muscle biopsy samples obtained from a cohort of patients with ME/CFS showed increased WASF3 protein levels and aberrant ER stress activation. In addition to revealing a potential mechanism for the bioenergetic deficiency in ME/CFS, our study may also provide insights into other disorders associated with fatigue such as rheumatic diseases and long COVID.
摘要：
肌痛性脑脊髓炎/慢性疲劳综合征（ME/CFS）的特征是各种致残症状，包括运动不耐受，并且在没有特定原因的情况下被诊断。使其临床管理具有挑战性。对这种明显的生物能量缺乏状态的分子机制的更好理解可以揭示开发靶向治疗策略的见解。我们报道Wiskott-Aldrich综合征蛋白家族成员3（WASF3）的过表达，在这里发现了一名38岁的妇女，患有长期的疲劳和运动不耐受，可以破坏线粒体呼吸超复合物的形成，并与内质网（ER）应激有关。转基因小鼠中WASF3的表达增加显着降低了其跑步机的跑步能力，同时伴有呼吸超复合物组装受损和骨骼肌线粒体中复合物IV水平降低。使用内毒素通过ER应激诱导WASF3，众所周知，与人类疲劳有关，也降低了小鼠的骨骼肌复合物IV水平，通过药物抑制内质网应激降低WASF3水平，改善慢性疲劳患者细胞的线粒体功能。扩大我们的发现，从一组ME/CFS患者中获得的骨骼肌活检样本显示WASF3蛋白水平升高和异常的ER应激激活。除了揭示ME/CFS中生物能缺乏的潜在机制外，我们的研究还可能提供与疲劳相关的其他疾病的见解，如风湿性疾病和长期COVID。
