Protection of rat skeletal muscle fibers by either L-carnitine or coenzyme Q10 against statins toxicity mediated by mitochondrial reactive oxygen generation

P G La Guardia,R R Catharino,F G Ravagnani,A E Vercesi,L C Alberici

doi:10.3389/fphys.2013.00103

Abstract

Mitochondrial redox imbalance has been implicated in mechanisms of aging, various degenerative diseases and drug-induced toxicity. Statins are safe and well-tolerated therapeutic drugs that occasionally induce myotoxicity such as myopathy and rhabdomyolysis. Previous studies indicate that myotoxicity caused by statins may be linked to impairment of mitochondrial functions. Here, we report that 1-h incubation of permeabilized rat soleus muscle fiber biopsies with increasing concentrations of simvastatin (1–40 μM) slowed the rates of ADP-or FCCP-stimulated respiration supported by glutamate/malate in a dose-dependent manner, but caused no changes in resting respiration rates. Simvastatin (1 μM) also inhibited the ADP-stimulated mitochondrial respiration supported by succinate by 24% but not by TMPD/ascorbate. Compatible with inhibition of respiration, 1 μM simvastatin stimulated lactate release from soleus muscle samples by 26%. Co-incubation of muscle samples with 1 mM L-carnitine, 100 μM mevalonate or 10 μM coenzyme Q10 (Co-Q10) abolished simvastatin effects on both mitochondrial glutamate/malate-supported respiration and lactate release. Simvastatin (1 μM) also caused a 2-fold increase in the rate of hydrogen peroxide generation and a decrease in Co-Q10 content by 44%. Mevalonate, Co-Q10 or L-carnitine protected against stimulation of hydrogen peroxide generation but only mevalonate prevented the decrease in Co-Q10 content. Thus, independently of Co-Q10 levels, L-carnitine prevented the toxic effects of simvastatin. This suggests that mitochondrial respiratory dysfunction induced by simvastatin, is associated with increased generation of superoxide, at the levels of complexes-I and II of the respiratory chain. In all cases the damage to these complexes, presumably at the level of 4Fe-4S clusters, is prevented by L-carnitine.

Highlights

Statins are natural or synthetic inhibitors of the enzyme HMG-CoA reductase that catalyzes the conversion of 3hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) into mevalonic acid, the rate-limiting step in cholesterol synthesis (Endo, 1992)
The inhibition caused by 1 μM simvastatin was 25 and 27% for Adenosine -diphosphate monopotassium salt dihydrate (ADP)- and FCCP-stimulated respiration, respectively
The inhibition peaked at 57% in the presence of 40 μM simvastatin for both ADP- and FCCP-stimulated respiration

Summary

Introduction

Statins are natural (fungal-derived) or synthetic inhibitors of the enzyme HMG-CoA reductase that catalyzes the conversion of 3hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) into mevalonic acid, the rate-limiting step in cholesterol synthesis (Endo, 1992). High plasma levels of cholesterol are well established as independent risk factor for coronary heart disease (Sirvent et al, 2005a) that can be significantly reduced by statins treatment (Tobert et al, 1982). The efficacy and tolerability of statins are well documented (Tobert et al, 1982; Sirvent et al, 2005b). This treatment normally lowers morbidity and mortality (LIPID Study Group, 1998) about 10% of the patients (Bruckert et al, 2005) develop myophatic symptoms and approximately one in 7.5 million patients develop fatal rhabdomyolysis (Venero and Thompson, 2009). Several studies using isolated mitochondria or intact cells propose that statins promote cell death mediated by mitochondrial dysfunctions associated with alterations in calcium homeostasis, inhibition of beta-oxidation, inhibition of complex I www.frontiersin.org

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