Effect of simvastatin on cholesterol metabolism in C2C12 myotubes and HepG2 cells, and consequences for statin-induced myopathy.
The mechanism of statin-induced skeletal muscle myopathy is poorly understood. We investigated how simvastatin affects cholesterol metabolism, ubiquinone levels, and the prenylation and N-linked glycosylation of proteins in C2C12 myotubes. We used liver HepG2 cells for comparison, as their responses to statins are well-characterized in terms of their cholesterol metabolism (in contrast to muscle cells), and statins are well-tolerated in the liver. Differences between the two cell lines could indicate the mechanism behind statin-induced myopathy. Simvastatin reduced de novo cholesterol production in C2C12 myotubes by 95% after 18h treatment. The reduction was 82% in the HepG2 cells. Total cholesterol pools, however, remained constant in both cell lines. Simvastatin treatment similarly did not affect total ubiquinone levels in the myotubes, unlike in HepG2 cells (22% reduction in CoQ10). Statin treatment reduced levels of Ras and Rap1 prenylation in both cell lines, whereas N-linked glycosylation was only affected in C2C12 myotubes (21% reduction in rate). From these observations, we conclude that total cholesterol and ubiquinone levels are unlikely to be involved in statin-mediated myopathy, but reductions in protein prenylation and especially N-linked glycosylation may play a role. This first comparison of the responses to simvastatin between liver and skeletal muscle cell lines may be important for future research directions concerning statin-induced myopathy.
Mullen
Peter James
PJ
Department of Research, University Hospital Basel, Switzerland. peter.mullen@unibas.ch
Lüscher
Barbara
B
Scharnagl
Hubert
H
Krähenbühl
Stephan
S
Brecht
Karin
K
D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D006031:Glycosylation; D056945:Hep G2 Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism / Q000633:toxicity*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009135:Muscular Diseases / Q000139:chemically induced*; D017368:Protein Prenylation; D012333:RNA, Messenger / Q000032:analysis; D011973:Receptors, LDL / Q000235:genetics; D019821:Simvastatin / Q000633:toxicity*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D014451:Ubiquinone / Q000032:analysis
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D011973:Receptors, LDL; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D014451:Ubiquinone; D002784:Cholesterol; D019821:Simvastatin