Simvastatin Has Profound Effects On Sarcoplasmic Reticulum Ca2+ Leak In Skeletal But Not Cardiac Muscle: A Mechanism For Myopathy

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 (Pu003c0.001), but had no effect on spark frequency and only a minor effect on duration (+26%; Pu003c0.001) in ventricular myocytes. Spark amplitude and width were not changed in either cell type. Thus the profound statin-induced SR Ca2+ leak in skeletal muscle is absent in cardiac myocytes. To determine whether simvastatin acutely induces SR leak in skeletal muscle, saponin-permeabilised cells from control animals were perfused with 10 µM simvastatin carboxylate (the active form) for 5 min. In FDB, simvastatin increased spark frequency (38%; Pu003c0.05) without significant effects on duration, amplitude or width. By contrast, in cardiac cells a minor reduction in frequency (17%) and amplitude (9%) were observed (Pu003c0.01). Together, these data show that simvastatin has disparate effects on SR Ca2+ release in skeletal and cardiac muscle. A possible mechanism which contributes to statin effects on the skeletal myocyte is direct interaction of the drug with RyR. In support of this, simvastatin carboxylate (10 µM) increased the open probability of single RyR channels derived from skeletal, but not cardiac, muscle (see Venturi et al. this meeting).Funded by the BHF