Abstract
Statins inhibit cholesterol biosynthesis and lower serum LDL-cholesterol levels. Statins are generally well tolerated, but can be associated with potentially life-threatening myopathy of unknown mechanism. We have shown previously that statins impair PGC-1β expression in human and rat skeletal muscle, suggesting that PGC-1β may play a role in statin-induced myopathy. PGC-1β is a transcriptional co-regulator controlling the expression of important genes in mitochondrial biogenesis, antioxidative capacity and energy metabolism. The principle aim of the current study was to investigate the interaction between atorvastatin and PGC-1β in more detail. We therefore treated wild-type mice and mice with selective skeletal muscle knockout of PGC-1β (PGC-1β(i)skm−/− mice) with oral atorvastatin (5 mg/kg/day) for 2 weeks. At the end of treatment, we determined body parameters, muscle function, structure, and composition as well as the function of muscle mitochondria, mitochondrial biogenesis and activation of apoptotic pathways. In wild-type mice, atorvastatin selectively impaired mitochondrial function in glycolytic muscle and caused a conversion of oxidative type IIA to glycolytic type IIB myofibers. Conversely, in oxidative muscle of wild-type mice, atorvastatin enhanced mitochondrial function via activation of mitochondrial biogenesis pathways and decreased apoptosis. In PGC-1β(i)skm−/− mice, atorvastatin induced a switch towards glycolytic fibers, caused mitochondrial dysfunction, increased mitochondrial ROS production, impaired mitochondrial proliferation and induced apoptosis in both glycolytic and oxidative skeletal muscle. Our work reveals that atorvastatin mainly affects glycolytic muscle in wild-type mice and demonstrates the importance of PGC-1β for oxidative muscle integrity during long-term exposure to a myotoxic agent.
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Abbreviations
- CK:
-
Creatine kinase
- FRL:
-
Free radical leak
- HMG-CoA:
-
3-Hydroxy-3-methylglutaryl-coenzyme A
- MHC:
-
Myosin heavy chain
- mtDNA:
-
Mitochondrial DNA
- NADH:
-
Nicotinamide adenine dinucleotide (reduced)
- OXPHOS:
-
Oxidative phosphorylation
- PGC:
-
Peroxisome proliferator-activated receptor-γ co-activator
- ROS:
-
Reactive oxygen species
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Acknowledgements
We thank the staff of the mouse facilities from Institut de Génétique et de Biologie Moléculaire et Cellulaire and Institut Clinique de la Souris from Illkirch in France. This work was supported by funds from the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the Collège de France, the Université de Strasbourg, the Agence Nationale de la Recherche (05-PCOD-032) and by French state funds through the Agence Nationale de la Recherche ANR-10-LABX-0030-INRT under the frame programme Investissements d’Avenir labelled ANR-10-IDEX-0002-02. G.L. was supported by the Agence Nationale de la Recherche (2010BLAN1108-01). SK was supported by a grant of the Swiss National Science Foundation (31003A_156270).
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FS, JZ, DM, BG, SK and BJ conceived and designed study, and FS, UD, ALC, MP, GL, and BJ performed experiments and analyzed data. FS, DM, TMW, BG, SK, and JB wrote the manuscript.
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Ethical approval: All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All animal experiments were approved by the Ethics Committee Com’Eth (Comité d’Ethique pour l’Expérimentation Animale, Strasbourg, France), and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
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Singh, F., Zoll, J., Duthaler, U. et al. PGC-1β modulates statin-associated myotoxicity in mice. Arch Toxicol 93, 487–504 (2019). https://doi.org/10.1007/s00204-018-2369-7
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DOI: https://doi.org/10.1007/s00204-018-2369-7