Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome.

Abstract

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 PPARδ 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.