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. 2012 Jun;33(11):1397-407.
doi: 10.1093/eurheartj/ehr224. Epub 2011 Jul 20.

Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a 'mitohormesis' mechanism involving reactive oxygen species and PGC-1

Jamal Bouitbir  1 , Anne-Laure Charles, Andoni Echaniz-Laguna, Michel Kindo, Frédéric Daussin, Johan Auwerx, François Piquard, Bernard Geny, Joffrey Zoll
Affiliations

Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a 'mitohormesis' mechanism involving reactive oxygen species and PGC-1

Jamal Bouitbir et al. Eur Heart J. 2012 Jun.

Abstract

Aims: Statins protect against cardiovascular-related mortality but induce skeletal muscle toxicity. To investigate mechanisms of statins, we tested the hypothesis that statins optimized cardiac mitochondrial function but impaired vulnerable skeletal muscle by inducing different level of reactive oxygen species (ROS).

Methods and results: In atrium of patients treated with statins, ROS production was decreased and oxidative capacities were enhanced together with an extensive augmentation of mRNAs expression of peroxisome proliferator-activated receptor gamma co-activator (PGC-1) family. However, in deltoid biopsies from patients with statin-induced muscular myopathy, oxidative capacities were decreased together with ROS increase and a collapse of PGC-1 mRNA expression. Several animal and cell culture experiments were conducted and showed by using ROS scavengers that ROS production was the triggering factor responsible of atorvastatin-induced activation of mitochondrial biogenesis pathway and improvement of antioxidant capacities in heart. Conversely, in skeletal muscle, the large augmentation of ROS production following treatment induced mitochondrial impairments, and reduced mitochondrial biogenesis mechanisms. Quercetin, an antioxidant molecule, was able to counteract skeletal muscle deleterious effects of atorvastatin in rat.

Conclusion: Our findings identify statins as a new activating factor of cardiac mitochondrial biogenesis and antioxidant capacities, and suggest the importance of ROS/PGC-1 signalling pathway as a key element in regulation of mitochondrial function in cardiac as well as skeletal muscles.

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Figures

Figure 1
Figure 1
Exploration of cardiac atrial muscle biopsies from patients treated (STAT group) or not (CONT group) with statins and of human muscle biopsies from patients with statin myopathy (M-STAT group) compared with control subjects (M-CONT group). (A) Representative pictures and quantification of reactive oxygen species fluorescence labelled with dihydroethidium. (B) PGC-1α and PGC-1β mRNA expression levels. (C) SOD1 and SOD2 mRNA expression levels. (D) Maximal mitochondrial respiration measured in the presence of ADP and glutamate/malate as substrates (Vmax). PGC-1α and -1β, peroxisome proliferator-activated receptor gamma co-activator 1 alpha and beta; SOD1, superoxide dismutase 1; SOD2, superoxide dismutase 2. Values were represented as mean ± SEM; n = 5–8 patients in each group, *P< 0.05; **P< 0.01 with unpaired t-test.
Figure 2
Figure 2
Atorvastatin treatment altered molecular pathway of mitochondrial biogenesis in muscles and antioxidant treatment abolished it in rats. Peroxisome proliferator-activated receptor gamma co-activator-1α (A), peroxisome proliferator-activated receptor gamma co-activator-1β (B), cytochrome oxidase 1 mRNA expression levels (C) and relative amount of mtDNA determined by real-time PCR (D) in cardiac and plantaris muscles. Values were represented as mean ± SEM; n = 8; *P< 0.05; **P< 0.01; ***P< 0.001 between groups with a two-way ANOVA followed by a Tukey post test.
Figure 3
Figure 3
Reactive oxygen species were reduced in cardiac muscle of rats after chronic atorvastatin treatment, but were largely increased in glycolytic one. (A) Total reactive oxygen species production measured by electron paramagnetic resonance in cardiac and plantaris muscles. (B) Representative pictures and quantification of reactive oxygen species fluorescence labelled with dihydroethidium in cardiac and plantaris muscles. (C) GSH measurement in cardiac and plantaris muscles. (D) The relative mRNA level of mitochondrial superoxide dismutase2 in cardiac and plantaris muscles. Values were represented as mean ± SEM; n = 8; *P< 0.05; **P< 0.01; ***P< 0.001 between groups with a two-way ANOVA followed by a Tukey post test.
Figure 4
Figure 4
Quercetin protected mitochondrial respiration of glycolytic muscle against deleterious effects of atorvastatin treatment in rats. Maximal mitochondrial respiration measured in the presence of ADP and glutamate/malate (Vmax; A) and succinate (Vsucc; B) as substrates in cardiac muscle and plantaris, respectively. Results were expressed as mean ± SEM; n = 8; *P< 0.05; **P< 0.01 between groups with a two-way ANOVA followed by a Tukey post test.
Figure 5
Figure 5
Atorvastatin induced expression of peroxisome proliferator-activated receptor gamma co-activator-1α mRNA expression levels by a mechanism implicating reactive oxygen species production in H9C2 cardiomyocytes. (A) Dihydroethidium staining in H9C2 cardiomyocytes treated with atorvastatin (1 µmol/L) during 48 and 72h in the presence or not of antioxidant molecule N-AcetylCysteine (1 mmol/L). (B) The mRNA expression level of peroxisome proliferator-activated receptor gamma co-activator-1α in different conditions. (C) The SOD2 mRNA level and protein concentration in different groups. (D) The TMRE-fluorescence intensity level in H9C2 cardiomyocytes exposed to doxorubicin (0.5 µmol/L) pre-treated or not with atorvastatin at different concentrations (0.5, 1, and 10 µmol/L). Values were represented as mean ± SEM; n = 4; *P < 0.05; **P < 0.01 atorvastatin condition vs. others groups in the same time incubation with a two-way ANOVA followed by a Tukey post test.
Figure 6
Figure 6
Atorvastatin decreased peroxisome proliferator-activated receptor gamma co-activator-1α mRNA expression levels due to the increase of reactive oxygen species level in L6 Woody myotubes. L6 myotubes were infected or not with adenovirus encoding peroxisome proliferator-activated receptor gamma co-activator-1α and were treated or not with atorvastatin (1 µmol/L) as well as of N-AcetylCysteine (1 mmol/L). We measured (A) Dihydroethidium staining, and (B) peroxisome proliferator-activated receptor gamma co-activator-1α mRNA expression in the different groups. Values were represented as mean ± SEM; n = 3; *P < 0.05 compared with all others conditions; **P < 0.01 compared with all other conditions with a one-way ANOVA followed by a Dunett post test.
Figure 7
Figure 7
In vitro atorvastatin increased slightly reactive oxygen species production in cardiac muscle, whereas it highly increased in plantaris muscle. Mitochondrial H2O2 emission in permeabilized fibres and total reactive oxygen species production measured by electron paramagnetic resonance were evaluated in cardiac (A and B, respectively) and plantaris muscles (C and D, respectively) after addition of 100µmol/L atorvastatin. Values represented in percentage of control; n = 7–10, *P< 0.05, and ***P< 0.001 vs. control with paired t-test.
Figure 8
Figure 8
Scheme illustrating the action of statins on mitochondrial function according to muscular phenotype. Statins acted through a ‘mitohormesis mechanism’ and protected oxidative cardiac muscle, by stimulating the mitochondrial biogenesis through mild oxidative stress and improved metabolic health. Conversely, when reactive oxygen species-detoxifying constituents were not sufficient to decrease the initial statin induced high-oxidative stress in glycolytic skeletal muscle, they induced mitochondrial dysfunctions, down-regulation of mitochondrial biogenesis and muscular pains or myopathy.
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