Abstract
Previous studies suggest that statins may disturb skeletal muscle lipid metabolism potentially causing lipotoxicity with insulin resistance. We investigated this possibility in wild-type mice (WT) and mice with skeletal muscle PGC-1α overexpression (PGC-1α OE mice). In WT mice, simvastatin had only minor effects on skeletal muscle lipid metabolism but reduced glucose uptake, indicating impaired insulin sensitivity. Muscle PGC-1α overexpression caused lipid droplet accumulation in skeletal muscle with increased expression of the fatty acid transporter CD36, fatty acid binding protein 4, perilipin 5 and CPT1b but without significant impairment of muscle glucose uptake. Simvastatin further increased the lipid droplet accumulation in PGC-1α OE mice and stimulated muscle glucose uptake. In conclusion, the impaired muscle glucose uptake in WT mice treated with simvastatin cannot be explained by lipotoxicity. PGC-1α OE mice are protected from lipotoxicity of fatty acids and triglycerides by increased the expression of FABP4, formation of lipid droplets and increased expression of CPT1b.
Highlights
Despite the availability of new treatment options, statins currently remain the mainstay for the treatment against hypercholesterolemia [1]
We have shown recently that mice with muscle PGC-1α overexpression (OE mice) treated with simvastatin were protected from impaired skeletal muscle mitochondrial dysfunction and impaired exercise capacity, suggesting a role of PGC-1α in preventing simvastatin-associated myotoxicity [30]
We investigated the effect of simvastatin on the plasma and skeletal lipid metabolism in wild-type mice and mice with muscle PGC-1α overexpression
Summary
Despite the availability of new treatment options, statins currently remain the mainstay for the treatment against hypercholesterolemia [1]. They are used mainly in the prevention and the treatment of cardiovascular diseases associated with dyslipidemia [2,3,4,5]. Statins have an excellent safety profile but are associated with skeletal muscle problems, a symptom complex called statin-associated muscle symptoms (SAMS) [7,8]. SAMS are associated with all statins on the market, with a higher prevalence for lipophilic statins such as simvastatin, possibly because of their capacity to reach extrahepatic tissues such as skeletal muscle [10,11].
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