Statins, inhibitors of HMG CoA reductase, are the most widely prescribed drugs for prevention of cardiovascular disease. The primary reason for cessation of statin therapy is skeletal myopathy but the underlying mechanism and apparent absence of detrimental effects of statins on cardiac muscle are not fully understood. We have previously reported that statin treatment in vivo in the rat causes a marked increase in Ca2+ spark frequency and duration in intact skeletal myocytes consistent with a profound leak of Ca2+ from the sarcoplasmic reticulum (SR). By contrast, only a minor increase in spark duration was seen in cardiac myocytes with equivalent statin treatment [1]. Here we investigate whether statins have acute direct effects on SR Ca2+ release which could contribute to differences in the susceptibility of skeletal and cardiac muscle to statin-induced Ca2+ leak. Flexor digitorum brevis (FDB) fibres and ventricular myocytes (VM) were isolated from male Wistar rats (220 ± 20g) by collagenase digestion. Cells were permeabilised by 2 min exposure to 0.005% saponin (FDB) or 12 min exposure to 0.01% saponin (VM), bathed in intracellular solution containing fluo-3 (50 µM for FDB and 10 µM for VM), and perfused with 10 µM simvastatin carboxylate (the active form) for 5 min. Control data were time-matched. Images were acquired in line-scan mode (every 6 ms). Ca2+ sparks were identified and analysed with ImageJ software (NIH) using the Sparkmaster plugin. Data are from 3-6 rats per group, and compared with the Student’s t-test. In FDB, simvastatin increased Ca2+ spark frequency (38%; P<0.05) without significant effects on duration, amplitude or width (n=53-70 cells from 6 animals). By contrast, in cardiac cells a minor reduction in frequency (17%) and amplitude (9%) was observed (P<0.01; n=57-61 cells from 3 animals). These data show that simvastatin has disparate effects on SR Ca2+ release in skeletal and cardiac muscle. In support of a direct interaction of statins with RyR, the SR Ca2+ release channel, simvastatin carboxylate (10 µM) increased the open probability of single RyR channels derived from skeletal, but not cardiac muscle (see poster by Venturi et al. this meeting). We propose that one reason for skeletal muscle sensitivity to statins’ effects is a direct activation of the RyR1 which induces SR Ca2+ leak – the starting point of a vicious cycle which culminates in myopathy. By contrast, cardiac myocytes are protected because of the lower sensitivity of RyR2 to statin activation. These data add to our understanding of the impact of statins on skeletal and cardiac muscle function and can be used in the development of strategies to improve statin compliance.