The role of mevalonate derived metabolites (isoprenoids) in statin-related myopathies

Abstract

The statins, inhibitors of 3‐hydroxy‐3‐methylglutaryl‐CoA reductase, are the mainstay of the treatment of hypercholesterolaemia, atherosclerosis and coronary artery disease. However, some patients develop myopathy which may be related to pre‐disposing factors such as high cellular statin uptake, or effects on other, non‐sterol isoprenoids, such as CoQ10, prenylation and geranylgeranylation of proteins, dolichols, or due to alterations in the distribution of cholesterol precursors. Mitochondrial dysfunction has been associated with statin‐related myopathy and it is possible that this arises secondary to inhibition of CoQ10 biosynthesis. This project was designed to develop methods for the measurement of CoQ10, and to enable differentiation between cholesterol precursors specific to the Bloch or Kandutsch‐Russell pathways. Tandem mass spectrometry was used to develop the CoQ10 assay and gas chromatograthy mass spectrometry was used for the quantitation of cholesterol and the sterol intermediates. These methods were then used to compare results from a large cohort of patients to test the hypothesis that modulated isoprenoid metabolism due to treatment with statins is involved in the aetiology of myopathy. To complement this the possible influence of statins in vitro was examined and showed decreased CoQ10 synthesis, together with evidence of increased mitochondrial superoxide production and an enhanced cellular mitochondrial mass. Despite this, using the parameters investigated in this study no definitive association to statin‐related myopathy could be found, suggesting this process is a complex one and further investigations are needed.