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Pilot Study of Peripheral Muscle Function in Primary Biliary Cirrhosis: Potential Implications for Fatigue Pathogenesis

Lookup NU author(s): Dr Kieren Hollingsworth, Professor Julia Newton, Professor Roy Taylor, Dr Claire McDonald, Dr Jeremy Palmer, Professor Andrew Blamire, Professor David Jones

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Abstract

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: 31P 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 encephalomyelitis, 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 r2 = 0.78, P < .005; PBC r2 = 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. Conclusions: 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. © 2008 AGA Institute.


Publication metadata

Author(s): Hollingsworth KG, Newton JL, Taylor R, McDonald C, Palmer JM, Blamire AM, Jones DEJ

Publication type: Article

Publication status: Published

Journal: Clinical Gastroenterology and Hepatology

Year: 2008

Volume: 6

Issue: 9

Pages: 1041-1048

Print publication date: 01/09/2008

Online publication date: 08/08/2008

ISSN (print): 1542-3565

ISSN (electronic): 1542-7714

Publisher: W.B. Saunders Co.

URL: http://dx.doi.org/10.1016/j.cgh.2008.04.013

DOI: 10.1016/j.cgh.2008.04.013


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