Skeletal muscle myopathy is the most common side effect of statins. It results in 25% of patients stopping treatment within 6 months (Jackevicius et al., 2002) with major implications for the incidence of cardiovascular disease. The mechanism of myopathy is not known but dysregulation of cytosolic Ca2+ concentration ([Ca2+]c) and mitochondrial dysfunction are the focus of the majority of studies. However, all work to date has used models which lack clinical relevance (in vitro statin treatment, saponin-skinned fibres). Here we determine for the first time the effect of chronic statin treatment in vivo on Ca2+ homeostasis in intact muscle fibres. Male Wistar rats were given simvastatin (40 mg/kg) daily by oral gavage over a 4 week period; control animals received saline. Flexor digitorum brevis fibres were isolated by collagenase digestion and loaded with fluo-4 AM. Data are given as mean ± S.E.M. of n cells from 4 rats, and compared with the Student’s t-test. Intact fibres from control animals showed few spontaneous Ca 2+ release events. By contrast, fibres from statin-treated rats exhibited more frequent Ca2+ sparks and embers (longer lasting events) which were larger in amplitude, width and duration than control fibres (Figure 1). Following introduction of the SERCA inhibitor cyclopiazonic acid (CPA; 20 µM), the slope of the [Ca2+]c increase was significantly higher in fibres from statin-treated animals compared with controls (0.0079 ± 0.0013 F/F0.s-1 vs. 0.0036 ± 0.0011 F/F0.s-1; P<0.05; n=13-17) consistent with increased leak of Ca2+ from the sarcoplasmic reticulum (SR) with statin treatment. Mitochondria may suppress spark/ember activity by buffering [Ca2+]c and controlling redox balance in the SR Ca2+ release channel (RyR1) environment. In support of this, Ru360 (20 µM) which blocks the mitochondrial Ca2+ uniporter (MCU) increased frequency, amplitude, width and duration of sparks/embers in control fibres (P<0.05; n=27-19). Interestingly, Ru360 had the opposite effect in statin fibres; decreased frequency, amplitude, width and duration of sparks/embers were recorded (P<0.05; n=33-63 cells from 4 rats). These data show for the first time that spontaneous Ca2+ release (leak) from the SR in intact muscle fibres is enhanced with statin treatment via a mechanism that depends on mitochondrial Ca2+ uptake. Ca2+ leak is a mechanism common to other skeletal myopathies (e.g. muscular dystrophy). Defining the cellular process that underlies statin induced myopathy is the first step in the development of co-therapies to improve statin compliance. Recent proposals for a reduction in the cardiovascular risk threshold for statin prescription by the National Institute for Health and Care Excellence could double statin use in the future, highlighting the importance of treating serious side-effects of these drugs.