Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome
Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome
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DOI：
10.1172/jci.insight.89376
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发表时间：
2016-12-22
期刊：
影响因子：
8
通讯作者：
Tronstad, Karl J.
中科院分区：
文献类型：
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作者：
Fluge, Oystein;Mella, Olav;Tronstad, Karl J.
肌痛性脑病/慢性疲劳综合征(ME/CFS)是一种病因不明的衰弱疾病，其显著症状包括劳后不适和恢复不良。代谢功能障碍是一个看似合理的因素。我们推测，血清氨基酸的变化可能揭示了ME/CFS能量代谢的特定缺陷。对200名ME/CFS患者和102名健康人的分析表明，通过TCA循环推动氧化代谢的氨基酸特异性减少，主要发生在女性ME/CFS患者中。内源性蛋白质分解代谢标志物3-甲基组氨酸在男性患者中显著升高。氨基酸模式提示丙酮酸脱氢酶(PDH)功能受损，支持抑制PDH激酶1、2和4、sirtuin 4和PPAR Delta在外周血单个核细胞中的表达增加。在重度ME/CFS患者的血清存在下生长的成肌细胞表现出代谢适应，包括线粒体呼吸增加和乳酸分泌过多。氨基酸的变化不能用症状严重程度、病程、年龄、体重指数或患者的体力活动水平来解释。这些发现与ME/CFS的临床表现是一致的，氧化磷酸化产生的ATP不足，而运动时产生的乳酸过多。
Myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is a debilitating disease of unknown etiology, with hallmark symptoms including postexertional malaise and poor recovery. Metabolic dysfunction is a plausible contributing factor. We hypothesized that changes in serum amino acids may disclose specific defects in energy metabolism in ME/CFS. Analysis in 200 ME/CFS patients and 102 healthy individuals showed a specific reduction of amino acids that fuel oxidative metabolism via the TCA cycle, mainly in female ME/CFS patients. Serum 3-methylhistidine, a marker of endogenous protein catabolism, was significantly increased in male patients. The amino acid pattern suggested functional impairment of pyruvate dehydrogenase (PDH), supported by increased mRNA expression of the inhibitory PDH kinases 1, 2, and 4; sirtuin 4; and PPAR delta in peripheral blood mononuclear cells from both sexes. Myoblasts grown in presence of serum from patients with severe ME/CFS showed metabolic adaptations, including increased mitochondrial respiration and excessive lactate secretion. The amino acid changes could not be explained by symptom severity, disease duration, age, BMI, or physical activity level among patients. These findings are in agreement with the clinical disease presentation of ME/CFS, with inadequate ATP generation by oxidative phosphorylation and excessive lactate generation upon exertion.