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Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a ‘mitohormesis’ mechanism involving reactive oxygen species and PGC-1
Open accessAbstract
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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“other studies have shown increased ROS production (3,42) and a decreased antioxidant capacity (3) with statin treatment.”
From Simvastatin Effects on Skeletal Muscle (2013) · cites this paper as [3]
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“Our findings of significantly reduced antioxidant capacity in combination with the known (3,40) elevated ROS production in the simvastatin-treated patients make it plausible that increased apoptosis could contribute to muscle pain in patients treated with statins.”
From Simvastatin Effects on Skeletal Muscle (2013) · cites this paper as [3]
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Metadata
- Authors
- Bouitbir, J., Charles, A.-L., Echaniz-Laguna, A., Kindo, M., Daussin, F., Auwerx, J., Piquard, F., Geny, B., & Zoll, J.
- Affiliations
- Hôpital Civil, Strasbourg (FR)
- École Polytechnique Fédérale de Lausanne (CH)
- Corresponding author
- Zoll, Joffrey
- Venue
- European Heart Journal
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-07-20
- Volume
- 33
- Issue
- 11
- Pages
- 1397-1407
- ISSN
- 0195-668X (ISSN-L)
- 1522-9645
- PMC
- PMC3365271
- OpenAlex
- W2102743559
- Cited by
- 256
- References
- 30
- Citations by year
- 2026: 8 · 2025: 17 · 2024: 13 · 2023: 14 · 2022: 18 · 2021: 12 · 2020: 24 · 2019: 22 · 2018: 18 · 2017: 22 · 2016: 25 · 2015: 18 · 2014: 9 · 2013: 17 · 2012: 16
- FWCI
- 5.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Heart Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- reroDoc Digital Library (submittedVersion)
- HAL (submittedVersion)
- edoc (University of Basel) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- National Science Foundation
- Institut National de la Santé et de la Recherche Médicale
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-59820, P01DK059820)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Coenzyme Q10 studies and effects
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- statins, atorvastatin, statin-induced myopathy, heart mitochondria, skeletal muscle mitochondria, reactive oxygen species, PGC-1, mitochondrial biogenesis, oxidative stress, antioxidant capacity, quercetin, mitohormesis, cardioprotection
- MeSH terms
- Atorvastatin, Animals, Antioxidants, Heart Atria, Heptanoic Acids, Humans, Male, Mitochondria, Heart, Mitochondria, Muscle, Pyrroles, Quercetin, RNA, Messenger, Superoxide Dismutase, Transcription Factors, Rats, Wistar, Reactive Oxygen Species, Muscle, Skeletal, Muscle Fibers, Skeletal, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Myocytes, Cardiac, Rats
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