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Cited by 116Mitochondrial Function and PathologyMuscle Physiology and DisordersCancer, Lipids, and Metabolism

Simvastatin induces impairment in skeletal muscle while heart is protected

Sirvent, Pascal, Bordenave, Sylvain, Vermaelen, Marianne, Roels, Belle, Vassort, Guy, Mercier, Jacques, Raynaud, Eric, Lacampagne, Alain·2005·Biochemical and Biophysical Research Communications
DOI 10.1016/j.bbrc.2005.10.108
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Abstract

3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are widely used to reduce plasma cholesterol concentration. However, statins are also known to induce various forms of muscular toxicity. We have previously shown that acute application of simvastatin on human skeletal muscle samples induced a cascade of cellular events originating from mitochondria and resulting in a global alteration of Ca2+ homeostasis. The present study was designed to further define the origin of the mitochondria impairment and to understand the apparent lack of deleterious effect on the heart. Using fluorescence imaging analysis and oxygraphy on human and rat skinned skeletal muscle samples, we show that the simvastatin-induced mitochondria impairment results from inhibition of the complex I of respiratory chain. Similar simvastatin-induced mitochondria impairment and alteration of Ca2+ homeostasis occur in permeabilized but not in intact ventricular rat cardiomyocytes. In intact rat skeletal muscle fibers from the flexor digitorum brevis muscle, the simvastatin-induced alteration of Ca2+ homeostasis is abolished when monocarboxylate transporter (MCT4) is inhibited. The impairment of complex I by simvastatin might be the primary step of its cellular deleterious effects leading to muscle fiber death. This mechanism is seen specifically in skeletal muscles. This specificity should be in part attributed to a preferential uptake of statins by MCT4 that is not expressed in cardiomyocytes.

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Crossref · 10.1016/j.bbrc.2005.10.108

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  • Acute statin treatment was reported to lower complex I-linked OXPHOS capacity in human skeletal muscle without affecting complex II-linked respiration.

    “The acute effect of statin treatment on mitochondrial oxidative phosphorylation (OXPHOS) capacity in human skeletal muscle has been investigated, and a decrease in OXPHOS capacity with complex I-linked substrates was reported, whereas respiration with complex II-linked substrates was unaffected (16).”

    From Simvastatin Effects on Skeletal Muscle (2013) · cites this paper as [16]

  • Acute statin effects have been studied in isolated mitochondria from L6 cells and skinned human and rat muscle, where simvastatin showed a toxic effect and depressed complex I respiration.

    “The acute effect of statins has, however, been studied in isolated mitochondria from L6 cells (a rat skeletal muscle cell line) (39) and in skinned human and rat muscle (16) in which a toxic effect of simvastatin and depressed complex I respiration was found.”

    From Simvastatin Effects on Skeletal Muscle (2013) · cites this paper as [16]

  • Statins decrease mitochondrial membrane potential in a dose-dependent manner.

    “Third, it has previously been reported that statins, in a dose-dependent manner, decrease the mitochondrial membrane potential (16,39).”

    From Simvastatin Effects on Skeletal Muscle (2013) · cites this paper as [16]

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Authors
Sirvent, P., Bordenave, S., Vermaelen, M., Roels, B., Vassort, G., Mercier, J., Raynaud, E., & Lacampagne, A.
Affiliations
  • Inserm (FR)
  • Université Montpellier 1 (FR)
Corresponding author
Lacampagne, Alain
ORCID
Venue
Biochemical and Biophysical Research Communications
Publisher
Elsevier BV
Published
2005-12
Volume
338
Issue
3
Pages
1426-1434
ISSN
0006-291X (ISSN-L)
DOI
10.1016/j.bbrc.2005.10.108
OpenAlex
W2089611661
Cited by
116
References
34
Citations by year
2026: 1 · 2025: 8 · 2024: 4 · 2023: 1 · 2022: 2 · 2021: 4 · 2020: 7 · 2019: 10 · 2018: 9 · 2017: 7 · 2016: 10 · 2015: 6 · 2014: 8 · 2013: 3 · 2012: 9
FWCI
1.87
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biochemical and Biophysical Research Communications (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Institut National de la Santé et de la Recherche Médicale
  • Fondation pour la Recherche Médicale
  • Agence Française de Sécurité Sanitaire des Produits de Santé
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
simvastatin, statin-induced myopathy, skeletal muscle, mitochondrial complex I inhibition, calcium homeostasis, MCT4, cardiomyocytes, statins, mitochondrial permeability transition
MeSH terms
Animals, Calcium, Cell Membrane, Cytosol, Electron Transport, Heart, Homeostasis, Humans, Male, Mitochondria, Heart, Myocardium, Rats, Wistar, Muscle, Skeletal, Simvastatin, Rats

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