UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Mitochondrial DNA alterations and statin-induced myopathy Stringer, Henry


Background/Objectives: Statins are widely used to treat hyperlipidemia and lower cardiovascular disease risk. While statins are generally well tolerated, ~10-15% of patients experience statin-induced myopathy (SIM), a potentially fatal complication. Statin treatment has been associated with mitochondrial dysfunction. High-dose simvastatin treatment has been associated with skeletal muscle mitochondrial DNA (mtDNA) depletion. The contribution of mitochondrial dysfunction to the development and exacerbation of SIM may be important. The goal of this project was to examine the effects of statins on mtDNA to provide further insight into the etiology and severity of mitochondrial myotoxicity in SIM. Methods/Results: Two studies were performed. PCR quantification of mtDNA and nuclear DNA was used to measure mtDNA content. Long-template PCR was used to amplify the mitochondrial genome and score mtDNA deletion burden. In an in vitro study, rhabdomyosarcoma cells were exposed to simvastatin and atorvastatin for over 70 days. Both mtDNA content and deletion burden were measured longitudinally and remained unchanged amongst statin treated cells. In an in vivo study, skeletal muscle biopsies from patients diagnosed with SIM (n=24) and comparators showing no pathologic findings (n=23) were retrospectively reviewed from stored clinical samples. The pathologic features and degree of pathology within each biopsy were scored. MtDNA content and deletion score was compared between groups. Two genotypes that are associated with changes in statin response and SIM risk, apolipoprotein E and SLCO1B1, were examined. No difference in genotype frequency between groups was detected. Controlling for age, gender, biopsy year and apolipoprotein E genotype, SIM subject mtDNA/nDNA (mean±SD, 2036±1146) was significantly lower than the comparators (3220±1594) (p=0.042). No difference was observed in mtDNA deletion score (0-200) between SIM subjects (21.2±19.2) and comparators (19.4±30.0). There was an inverse correlation between mtDNA content and degree of pathology (p=006 r=-0.399). Conclusions: We found decreased in vivo skeletal muscle mtDNA content in association with SIM. How this relates to the pathogenesis of SIM remains unclear. As the mtDNA deletion score was not associated with SIM, quantitative rather than qualitative mtDNA alterations are suggested. MtDNA content should be further investigated as a potential marker of statin drug myotoxicity.

Item Media

Item Citations and Data


Attribution-NonCommercial-NoDerivatives 4.0 International