Cellular cholesterol is regulated by uptake, de novo synthesis, storage and efflux. Statins are inhibitors of HMG CoA reductase, an enzyme governing the rate limiting step in cholesterol synthesis. Statin treatment will initially decrease free cellular cholesterol but this in turn will promote expression of proteins responsible for cholesterol uptake (LDL receptors) and synthesis (HMG CoA reductase) and decrease expression of proteins involved in its storage as cholesteryl esters (acyl CoA cholesterol transferase) and efflux (caveolin) via sterol regulatory elements (SRE) in promoter regions. It has recently been shown that cholesterol efflux pathways are the main means by which (neonatal) cardiac myocytes regulate their cholesterol (Reboulleau et al., 2012). We have compared the effect of acute and chronic statin treatment on cardiac and skeletal muscle. In adult rat ventricular myocytes exposed to 10 µM simvastatin for 48 h in culture, cholesterol levels were reduced by 30%, and a corresponding decrease in caveolin 3 expression was seen (cells from n=3-4 hearts; P<0.05; Student’s t-test). By contrast, myocardium from adult rats treated with 40 mg/kg simvastatin by oral gavage daily for 2 weeks showed no change in cholesterol (0.38 ± 0.01 vs. 0.38 ± 0.02 µg/mg total protein; n=6 hearts; P>0.05). Despite this, caveolin 3 expression was reduced by 40% in statin-treated animals (P<0.05). These data are consistent with the concept that, following 2 weeks of statin treatment, SRE-dependent decreases in caveolin 3 expression act to return cellular cholesterol to normal levels by attenuating efflux pathways. However, normalisation of cholesterol at this time point is not common to all muscle. In gastrocnemius type II skeletal muscle from the same group of animals, cholesterol levels were lowered by 70% (P<0.05), despite an equivalent reduction in caveolin 3 expression (P<0.05). This indicates that skeletal muscle lacks the ability to regulate cholesterol homeostasis to the extent observed in cardiac muscle. Our data suggest that the effects of statins are temporally defined, with acute statin treatment in vitro providing a snapshot of early cardiac statin effects before SRE-dependent changes in caveolin expression are able to normalise cholesterol by attenuating its efflux. Skeletal muscle lacks the cholesterol homeostatic mechanisms of cardiac muscle and is therefore more susceptible to statin-induced damage by long term cholesterol depletion. The marked decrease in both cholesterol and caveolin, two essential elements of caveolae, in statin-treated skeletal muscle may be a mechanism underlying statin-induced myopathy.