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 on cardiac muscle function is not understood. Here, we compare the effect of chronic statin treatment in vitro on Ca2+ sparks in heart and intact skeletal muscle. Male Wistar rats were given simvastatin (40 mg/kg) daily by oral gavage over a 4 week period; control animals received saline. Ventricular myocytes and flexor digitorum brevis (FDB) fibres were isolated by collagenase digestion and loaded with fluo-4 AM. Data are given as mean ± S.E.M. of 62-109 cells from 5-11 rats, and compared with the Student’s t-test. As previously reported 1, few spontaneous Ca2+ release events were present in FDB fibres from control animals (0.22 ± 0.04 events/100μm/sec). By contrast, an increased incidence of spontaneous Ca2+ sparks and embers was present in FDB fibres from statin-treated rats (0.82 ± 0.10 events/100µm/sec; P<0.001 vs. control), which were identical (P>0.05) in amplitude (0.31 ± 0.01 vs. 0.29 ± 0.02 F/F0) and width (1.07 ± 0.03 vs. 1.03 ± 0.06 µm) but longer in duration (130 ± 12 vs. 54 ± 5 ms; P<0.01) than events in control animals. By contrast, in ventricular myocytes, statin treatment had no effect (P>0.05) on spark frequency (4.6 ± 0.3 vs. 4.8 ± 0.3 events/100µm/sec), amplitude (1.63 ± 0.02 vs. 1.66 ± 0.02 F/F0) or width (2.43 ± 0.05 vs. 2.42 ± 0.05 µm) but slightly increased duration (70 ± 4 vs. 55 ± 3 ms; P<0.01). Statins had no effect on the occurrence of spontaneous waves in these cells. In electrically paced cardiac myocytes, the amplitude of the Ca2+ transient was significantly reduced by statin treatment (5.9 ± 0.2 vs. 6.7 ± 0.3 F/F0; P<0.05). We have previously shown an identical effect of treating ventricular myocytes with simvastatin in vitro for 48 h 2. These data show that statin treatment markedly increases Ca2+ leak from the sarcoplasmic reticulum (SR) in skeletal muscle through increased spark frequency and duration. Increased SR leak is common to other types of skeletal myopathy (e.g. muscular dystrophy). Here for the first time we show that statins also increase the duration of Ca2+ sparks in cardiac cells. This effect might reduce SR Ca2+ load, contributing to the observed decrease in Ca2+ transient amplitude. The reason why skeletal muscle is more sensitive to statins effects and the full impact of statins on cardiac muscle function remains to be established.