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

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.

Efficiency of hepatocyte pretreatment with coenzyme Q10 against statin toxicity

“…We already know that CoQ 10 participates in the electron transport chain in mitochondria (27) and that statins can interfere with CoQ 10 , compromising cellular energy production (28). La Guardia et al (29) have demonstrated that simvastatin inhibits mitochondrial respiration, depletes CoQ 10 , and increases hydrogen peroxide production. A small increase in CoQ 10 concentration in mitochondrial membranes can therefore restore mitochondrial respiration (7) as one of the mechanisms to protect liver cells from statin toxicity.…”

Pravastatin Chronic Treatment Sensitizes Hypercholesterolemic Mice Muscle to Mitochondrial Permeability Transition: Protection by Creatine or Coenzyme Q10

“…Although the molecular mechanisms underlying statin-induced myotoxicity are not yet fully understood, a common hypothesis suggests that it is mediated by inhibition of mitochondrial respiration as a consequence of CoQ 10 depletion (Päivä et al, 2005; Bookstaver et al, 2012; Larsen et al, 2013). In addition, previous studies propose that statins cause cell death associated with alterations in calcium homeostasis, inhibition of beta-oxidation, inhibition of mitochondrial respiratory complexes I and II followed by mitochondrial oxidative stress (Kaufmann et al, 2006; Oliveira et al, 2008; Costa et al, 2013; La Guardia et al, 2013) and also inhibition of complex III (Schirris et al, 2015). We have previously shown that statins stimulate Ca 2+ induced mitochondrial permeability transition (MPT) in mitochondria isolated from murine liver and muscle, and from mice treated with lovastatin (Velho et al, 2006).…”

l-Carnitine, but not coenzyme Q10, enhances the anti-osteoporotic effect of atorvastatin in ovariectomized rats

“…Estrogen protects skeletal muscles through its antioxidant effect (Sotiriadou et al, 2003). Statins' myopathy, mainly postulated to cause oxidative damage of the mitochondrial respiratory chains, is reversed by L-carnitine and CoQ10 through their direct radical scavenging effects (La Guardia et al, 2013). Simvastatin's myopathy impairs phosphatidylinositol 3-kinase/Akt signaling in rodent skeletal muscle (Mallinson et al, 2012).…”

“…L-Carnitine, besides its metabolic role, has an antioxidant effect and can directly decrease superoxide radical generation. CoQ10 is an essential electron transporter in the respiratory chain and its reduced form (ubiquinol) shows antioxidant properties (Young et al, 2011;Bookstaver et al, 2012;La Guardia et al, 2013). Simvastatin increases cytoplasmic Ca 2+ triggering mitochondrial reactive oxygen generation and myotoxicity (Sirvent et al, 2005a).…”