title: Decreased skeletal muscle mitochondrial DNA in patients with statin-induced myopathy.
abstract: Statins are widely used to treat hyperlipidemia and lower cardiovascular disease risk. While statins are generally well tolerated, some patients experience statin-induced myopathy (SIM). Statin treatment has been associated with mitochondrial dysfunction and mitochondrial DNA (mtDNA) depletion. In this retrospective study, skeletal muscle biopsies from patients diagnosed with SIM were studied. These were compared with biopsies from patients clinically assessed as having statin-unrelated myopathy but whose biopsy showed no or negligible pathology. For each biopsy sample, mtDNA was quantified relative to nuclear DNA (mtDNA content) by qPCR, mtDNA deletions were investigated by long-template PCR followed by gel densitometry, and mtDNA oxidative damage was quantified using a qPCR-based assay. For a subset of matched samples, mtDNA heteroplasmy and mutations were investigated by cloning/sequencing. Skeletal muscle mtDNA content was significantly lower in SIM patients (N=23, mean±SD, 2036±1146) than in comparators (N=24, 3220±1594), p=0.006. There was no difference in mtDNA deletion score or oxidative mtDNA damage between the two groups, and no evidence of increased mtDNA heteroplasmy or somatic mutations was detected. The significant difference in skeletal muscle mtDNA suggests that SIM or statin treatments are associated with depletion of skeletal muscle mtDNA or that patients with an underlying predisposition to SIM have lower mtDNA levels. If statins induce mtDNA depletion, this would likely reflect decreased mitochondria biogenesis and/or increased mitochondria autophagy. Further work is necessary to distinguish between the lower mtDNA as a predisposition to SIM or an effect of SIM or statin treatment.
authors: University of British Columbia, Department of Pathology & Laboratory Medicine, G227-2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T2B5. hstring@interchange.ubc.ca
authors: Henry A J
authors: HA
authors: Stringer
authors: Gurmeet K
authors: GK
authors: Sohi
authors: John A
authors: JA
authors: Maguire
authors: Hélène C F
authors: HC
authors: Côté
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D003430:Cross-Sectional Studies; D004272:DNA, Mitochondrial / Q000096:biosynthesis / Q000235:genetics; D016208:Databases, Factual; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009135:Muscular Diseases / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism*; D012189:Retrospective Studies
chemical_list: D004272:DNA, Mitochondrial; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors