Effect of a high dose of simvastatin on muscle mitochondrial metabolism and calcium signaling in healthy volunteers

Galtier, Florence; Mura, Thibault; Mauverger, Éric Raynaud de; Chevassus, Hugues; Farret, Anne; Gagnol, J. P.; Costa, Fábio Luiz Paranhos; Dupuy, Aude; Petit, Pierre; Cristol, Jean Paul; Mercier, Jacques; Lacampagne, Alain

doi:10.1016/j.taap.2012.06.020

Cited by 46 publications

(33 citation statements)

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“…Given PDC is key to the regulation of mitochondrial CHO oxidation, it is interesting to note that in line with our observations reported here mitochondrial dysfunction is evident in models of statin myopathy (Bouitbir et al 2011; Mullen et al 2011; Galtier et al 2012; Kwak et al 2012). Specifically, skeletal muscle tissue from patients receiving statin therapy shows impaired mitochondrial respiration restricted to mainly complex I of the respiratory chain (Sirvent et al 2012).…”

Section: Discussionsupporting

confidence: 87%

Pharmacological activation of the pyruvate dehydrogenase complex reduces statin‐mediated upregulation of FOXO gene targets and protects against statin myopathy in rodents

Mallinson

Constantin‐Teodosiu

Glaves

et al. 2012

The Journal of Physiology

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Key points• Statin myopathy impairs phosphatidylinositol 3-kinase/Akt signalling and activates forkhead box protein O (FOXO) transcription factors in vivo in rodent skeletal muscle. This is associated with upregulation of downstream gene targets known to increase proteasomal and lysosomal-mediated protein breakdown, oxidative stress and inflammation, and inhibit muscle carbohydrate (CHO) oxidation.• We hypothesised that forcibly increasing muscle CHO oxidation in vivo, using the pyruvate dehydrogenase complex activator, dichloroacetate (DCA), would blunt statin-mediated increases in mRNA expression of these FOXO gene targets, thereby reducing statin myopathy.• Chronic administration of DCA with simvastatin dampened statin-mediated increases in muscle atrophy F-box (MAFbx), cathepsin-L and pyruvate dehydrogenase kinase-4 mRNA in a dose-dependent manner, which was corroborated by protein activity and expression measurements, and blunted statin myopathy.• These results provide convincing evidence that pharmacologically increasing muscle CHO oxidation reduces simvastatin-induced myopathy by dampening the upregulation of genes known to increase proteasomal and lysosomal protein breakdown and inhibit CHO oxidation.Abstract We previously reported that statin myopathy is associated with impaired carbohydrate (CHO) oxidation in fast-twitch rodent skeletal muscle, which we hypothesised occurred as a result of forkhead box protein O1 (FOXO1) mediated upregulation of pyruvate dehydrogenase kinase-4 (PDK4) gene transcription. Upregulation of FOXO gene targets known to regulate proteasomal and lysosomal muscle protein breakdown was also evident. We hypothesised that increasing CHO oxidation in vivo, using the pyruvate dehydrogenase complex (PDC) activator, dichloroacetate (DCA), would blunt activation of FOXO gene targets and reduce statin myopathy. Female Wistar Hanover rats were dosed daily for 12 days (oral gavage) with either vehicle (control, 0.5% w/v hydroxypropyl-methylcellulose 0.1% w/v polysorbate-80; n = 9), 88 mg kg −1 day −1 simvastatin (n = 8), 88 mg kg −1 day −1 simvastatin + 30 mg kg −1 day −1 DCA (n = 9) or 88 mg kg −1 day −1 simvastatin + 40 mg kg −1 day −1 DCA (n = 9). Compared with control, simvastatin reduced body mass gain and food intake, increased muscle fibre necrosis, plasma creatine kinase levels, muscle PDK4, muscle atrophy F-box (MAFbx) and cathepsin-L mRNA expression, increased PDK4 protein expression, and proteasome and cathepsin-L activity, and reduced muscle PDC activity. Simvastatin with DCA maintained body mass gain and food intake, abrogated the myopathy, decreased muscle PDK4 mRNA and protein, MAFbx and cathepsin-L mRNA, increased activity of PDC and reduced proteasome activity compared with simvastatin. PDC activation abolished statin myopathy in rodent skeletal muscle, which occurred at least in part via inhibition of FOXO-mediated transcription of genes regulating muscle CHO utilisation and protein breakdown.

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Section: Discussionsupporting

confidence: 87%

Pharmacological activation of the pyruvate dehydrogenase complex reduces statin‐mediated upregulation of FOXO gene targets and protects against statin myopathy in rodents

Mallinson

Constantin‐Teodosiu

Glaves

et al. 2012

The Journal of Physiology

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“…Galtier et al have reported that in healthy volunteers who received a high dose of simvastatin (80 mg/d), subjects with the highest creatine kinase increase displayed alterations in mitochondrial respiration and muscle calcium homeostasis, as reflected by a significantly lower Vmax rotenone succinate and an increase in Ca 2+ spark amplitude, respectively [31]. Also, several studies have shown that simvastatin-induced mitochondrial dysfunction leads to increased oxidative stress resulting in induction of PGC-1α, which is an important regulator of mitochondrial biogenesis and metabolism [28].…”

Section: Discussionmentioning

confidence: 99%

Effects of Lipid-Lowering Drugs on Irisin in Human Subjects In Vivo and in Human Skeletal Muscle Cells Ex Vivo

et al. 2013

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Context and ObjectiveThe myokine irisin has been proposed to regulate energy homeostasis. Little is known about its association with metabolic parameters and especially with parameters influencing pathways of lipid metabolism. In the context of a clinical trial, an exploratory post hoc analysis has been performed in healthy subjects to determine whether simvastatin and/or ezetimibe influence serum irisin levels. The direct effects of simvastatin on irisin were also examined in primary human skeletal muscle cells (HSKMCs).Design and ParticipantsA randomized, parallel 3-group study was performed in 72 men with mild hypercholesterolemia and without apparent cardiovascular disease. Each group of 24 subjects received a 14-day treatment with either simvastatin 40 mg, ezetimibe 10 mg, or their combination.ResultsBaseline irisin concentrations were not significantly correlated with age, BMI, estimated GFR, thyroid parameters, glucose, insulin, lipoproteins, non-cholesterol sterols, adipokines, inflammation markers and various molecular markers of cholesterol metabolism. Circulating irisin increased significantly in simvastatin-treated but not in ezetimibe-treated subjects. The changes were independent of changes in LDL-cholesterol and were not correlated with changes in creatine kinase levels. In HSKMCs, simvastatin significantly increased irisin secretion as well as mRNA expression of its parent peptide hormone FNDC5. Simvastatin significantly induced cellular reactive oxygen species levels along with expression of pro- and anti-oxidative genes such as Nox2, and MnSOD and catalase, respectively. Markers of cellular stress such as atrogin-1 mRNA and Bax protein expression were also induced by simvastatin. Decreased cell viability and increased irisin secretion by simvastatin was reversed by antioxidant mito-TEMPO, implying in part that irisin is secreted as a result of increased mitochondrial oxidative stress and subsequent myocyte damage.ConclusionsSimvastatin increases irisin concentrations in vivo and in vitro. It remains to be determined whether this increase is a result of muscle damage or a protective mechanism against simvastatin-induced cellular stress.Trial RegistrationClinicalTrials.gov NCT00317993 NCT00317993.

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“…This possibility is supported by the advanced report that (S)- [6]-gingerol treatment significantly increased Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α (PGC-1α) mRNA expression within 5 hours in L6 myotubes and markedly increased mitochondrial content detected at a later time [53] . PGC-1αis considered a key "master regulator" of mitochondrial biogenesis (replication) in tissues active in oxidative metabolism as the liver and the skeletal muscles [54] .…”

Section: Discussionmentioning

confidence: 77%

“…Although, the histological and biophysiological changes-induced by simvastatin might be of multifactorial origin, the oxidative stress effect has been greatly suggested [56] . This suggestion is reinforced by our physiological findings that showed decreased serum total antioxidant capacity (TAC), increased serum (CK), serum total peroxide (TP) and increased oxidative stress index (OXI) in simvastatin-treated animal group as compared to control group.…”

Section: Discussionmentioning

confidence: 99%

“…Risk factors for the development of a statin-induced myopathy include high dosages, increasing age, female sex, renal and hepatic insufficiency, diabetes mellitus and concomitant therapy with drugs such as fibrates, cyclosporine, macrolide antibiotics, warfarin and digoxin [5] . Statins decreased membrane cholesterol and thereby affecting membrane ionic channels and disrupting calcium handling [6,7] . Moreover, statins induced muscle-specific mitochondrial impairment and oxidative stress [2] .Vitamin E (tocopherol) is considered a major fat soluble antioxidant and is commonly used to combat the injury and oxidative stress associated with exercise as a nutritional antioxidant [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

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The Possible Protective Role of Ginger Extract Versus Vitamin E Against Simvastatin-Induced Skeletal Myotoxicity in Adult Male Albino Rats: Histological, Physiological and Biochemical Study

Hamid¹,

Mola²,

Meligy³

et al. 2017

Egyptian Journal of Histology

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Introduction: Statins are group of drugs used to reduce total and low density lipoprotein (LDL)-cholesterol level and to reduce the morbidity and mortality of cardiovascular diseases. Meanwhile, induced skeletal muscle-specific mitochondrial impairment, oxidative stress and myotoxicity are serious side effects . Vitamin E and ginger extract are well known potent antioxidants. Aim: To study the possible protective effect of ginger extract versus vitamin E against simvastatin-induced skeletal muscle histological and the associated biophysiological changes. Materials and Methods: Forty adult male albino rats were randomly divided into four equal groups (10 rats, each).; Group 1: was the control rats. Group 2: received 0.54 mg/kg/day simvastatin orally for 8 weeks. Group 3: received concomitant treatment of simvastatin and 30 mg/kg/day vitamin E orally for 8 weeks. Group 4 received concomitant treatment of simvastatin and 500mg/kg/day ginger extract orally for 8 weeks. After sacrifice, specimens were taken from the belly of the quadriceps femoris muscles of all animal groups and processed for light and electron microscopy. Biochemical tests and statistical analysis were done. Results: Group 2 showed focal areas of muscle fiber loss, mononuclear cellular infiltration and variable staining density. Ultra structurally, myofibrillar degeneration and accumulation of numerous giant infrequently damaged mitochondria were observed. The skeletal muscle fibers of animals from group 3 and group 4, both were markedly improved. Group 4 revealed obviously normal mitochondria. Conclusion: Administration of simvastatin for 8 weeks induced histological, physiological and biochemical skeletal myotoxic effects. These effects were greatly ameliorated by concomitant administration vitamin E or ginger extract. Ginger extract was more effective.

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Effect of a high dose of simvastatin on muscle mitochondrial metabolism and calcium signaling in healthy volunteers

Cited by 46 publications

References 31 publications

Pharmacological activation of the pyruvate dehydrogenase complex reduces statin‐mediated upregulation of FOXO gene targets and protects against statin myopathy in rodents

Pharmacological activation of the pyruvate dehydrogenase complex reduces statin‐mediated upregulation of FOXO gene targets and protects against statin myopathy in rodents

Effects of Lipid-Lowering Drugs on Irisin in Human Subjects In Vivo and in Human Skeletal Muscle Cells Ex Vivo

The Possible Protective Role of Ginger Extract Versus Vitamin E Against Simvastatin-Induced Skeletal Myotoxicity in Adult Male Albino Rats: Histological, Physiological and Biochemical Study

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