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 reported that statin treatment in vivo causes a profound leak of Ca2+ from the sarcoplasmic reticulum (SR) of intact skeletal myocytes, a common myopathic mechanism. Here we compare the effect of simvastatin on Ca2+ sparks in rat skeletal and cardiac myocytes. Simvastatin treatment in vivo (40 mg/kg/day for 4 weeks) markedly increased Ca2+ spark frequency (280%) and duration (140%) in fluo4-loaded flexor digitorum brevis (FDB)fibres (P