Pilot study of peripheral muscle function in primary biliary cirrhosis: Potential implications for fatigue pathogenesis
Pilot study of peripheral muscle function in primary biliary cirrhosis: Potential implications for fatigue pathogenesis
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DOI：
10.1016/j.cgh.2008.04.013
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发表时间：
2008-09-01
影响因子：
12.6
通讯作者：
Jones, David E. J.
中科院分区：
文献类型：
--
作者：
Hollingsworth, Kieren G.;Newton, Julia L.;Jones, David E. J.
背景和目标：原发性胆汁性肝硬化（PBC）的特点是95%的患者的自身抗体反应针对线粒体抗原丙酮酸脱氢酶复合物（PDC）。尽管抗PDC在体外抑制PDC功能，但在PBC中的体内线粒体功能尚未被检查。研究方法：在PBC患者（n = 15）和疲劳（慢性疲劳综合征/肌痛性脑脊髓炎，n = 8），胆汁淤积（原发性硬化性胆管炎[PSC]，n = 4）和正常（n = 8）对照组中进行P-31磁共振波谱分析，以确定在25%和35%的最大随意收缩运动期间外周肌的线粒体功能和pH调节。结果如下：正常、慢性疲劳综合征/肌痛性脑脊髓瘤和PSC受试者在低强度运动后，二磷酸腺苷（ADP）和磷酸肌酸（PCr）恢复动力学之间均显示出密切的相关性，反映了线粒体对ADP“驱动”的PCr“反应”的正常严格调节。PBC患者中这种关系消失，表明线粒体功能障碍（正常r（2）= 0.78，P <0.005; PBC r（2）= 0.007，P = ns）。PCr和ADP恢复半衰期之间的比值（对照组恒定，表明正常的线粒体反应性）在PBC患者（但不是PSC）中显著升高，并与抗PDC水平相关。在较高水平的运动PBC（但不是PSC）患者表现出过度的肌肉酸中毒，与PH与升高的PCr/ADP恢复率，表明线粒体功能障碍的链接。PBC患者运动后肌肉pH恢复时间也显著延长（与线粒体功能无关），与临床疲劳相关。结论：PBC患者表现出不同程度的肌肉线粒体功能障碍，表现为运动后过度酸中毒。病人能从酸中毒中迅速恢复的程度似乎决定了他们是否有临床疲劳。
Background & Aims: Primary biliary cirrhosis (PBC) is characterized in 95% of patients by autoantibody responses directed against the mitochondrial antigen pyruvate dehydrogenase complex (PDC). Although anti-PDC inhibits PDC function in vitro, mitochondrial function in vivo in PBC has not been examined. Methods: P-31 magnetic resonance spectroscopy was performed in PBC patients (n = 15) and fatigued (chronic fatigue syndrome/myalgic encephalomyelitis, n = 8), cholestatic (primary sclerosing cholangitis [PSC], n = 4), and normal (n = 8) controls to define mitochondrial function and pH regulation in peripheral muscle during exercise at 25% and 35% of maximum voluntary contraction. Results: Normal, chronic fatigue syndrome/myalgic encephalomyelids, and PSC subjects all showed close correlation between kinetics of adenosine diphosphate (ADP) and phosphocreatine (PCr) recovery after low-impact exercise, reflecting the normal tight regulation of PCr "response" by mitochondria to ADP "drive." This relationship was lost in PBC patients, indicating mitochondrial dysfunction (normal r(2) = 0.78, P < .005; PBC r(2) = 0.007, P = ns). Ratio between PCr and ADP recovery half-times (constant in controls, indicating normal mitochondrial responsivity) was significantly elevated in PBC patients (but not PSC) and was associated with anti-PDC levels. At higher levels of exercise PBC (but not PSC) patients showed excess muscle acidosis, with PH correlating with elevation of PCr/ADP recovery ratio, indicating a link to mitochondrial dysfunction. PBC patients alone also showed significant prolongation of muscle pH recovery time after exercise (unrelated to mitochondrial function), which correlated with clinical fatigue. Conclusion : PBC patients exhibit a variable degree of muscle mitochondrial dysfunction that manifests as excess acidosis after exercise. The, extent to which patients can recover rapidly from acidosis appears to determine whether they are clinically fatigued.