Statin Induced Myopathy: A Role for Mitochondrial Ca2+ and No in Enhanced Sarcoplasmic Reticulum Ca2+ Leak

Abstract

The need to understand the mechanism of statin-induced myopathy is increasing as the cardiovascular risk threshold for statin prescription is reduced across the globe. Here we determine for the first time the effect of chronic statin treatment in vivo (simvastatin 40 mg/kg/day by oral gavage over a 4 week period) on Ca2+ homeostasis in intact (non-permeabilised) type II rat skeletal muscle fibres, and investigate a role for mitochondria and NO. In fluo-4 loaded FDB fibres, sarcoplasmic reticulum (SR) Ca2+ leak (indexed in the presence of the SERCA inhibitor cyclopiazonic acid) was significantly higher (P<0.05) following statin treatment. This could be explained by the observed increase (P<0.001) in the frequency and duration of Ca2+ sparks/embers in statin fibres. Interestingly, inhibition of the mitochondrial Ca2+ uniporter by Ru360 in statin fibres normalised spark frequency and duration to control levels (P<0.05), suggesting that mitochondrial Ca2+ uptake contributes to statin effects on SR Ca2+ release. NOS inhibition with L-NAME had a greater impact (P<0.05) on NO (indexed with DAF-2) in statin fibres compared with controls, suggesting increased NOS activity with statin treatment. This is consistent with reduced expression (P<0.05) of GAPDH-normalised caveolin 1 and 3 in gastrocnemius muscle from statin treated animals; caveolins are the main constitutive inhibitors of nNOS and eNOS. Together these data show for the first time that statin treatment enhances SR Ca2+ leak in intact muscle fibres. We propose that Ca2+-dependent mitochondrial ROS production and NO modify RyR to effect this leak. Defining the cellular processes that underlie statin induced myopathy is the first step in the development of co-therapies to improve statin compliance. Sponsored by the British Heart Foundation.