Archives of Toxicology

, Volume 93, Issue 2, pp 487–504 | Cite as

PGC-1β modulates statin-associated myotoxicity in mice

  • François Singh
  • Joffrey Zoll
  • Urs Duthaler
  • Anne-Laure Charles
  • Miljenko V. Panajatovic
  • Gilles Laverny
  • Thomas G. McWilliams
  • Daniel Metzger
  • Bernard Geny
  • Stephan Krähenbühl
  • Jamal BouitbirEmail author
Organ Toxicity and Mechanisms


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.


Atorvastatin Myopathy PGC-1β Apoptosis Reactive oxygen species (ROS) Mitochondrial proliferation 



Creatine kinase


Free radical leak


3-Hydroxy-3-methylglutaryl-coenzyme A


Myosin heavy chain


Mitochondrial DNA


Nicotinamide adenine dinucleotide (reduced)


Oxidative phosphorylation


Peroxisome proliferator-activated receptor-γ co-activator


Reactive oxygen species



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).

Author contributions

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.

Compliance with ethical standards

Ethical standards

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.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

204_2018_2369_MOESM1_ESM.docx (17 kb)
Supplementary material 1 (DOCX 16 KB)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Clinical Pharmacology and Toxicology, Department of BiomedicineUniversity HospitalBaselSwitzerland
  2. 2.Université de Strasbourg, Fédération de Médecine Translationnelle, Equipe d’Accueil 3072, Institut de Physiologie, Faculté de MédecineStrasbourgFrance
  3. 3.Swiss Centre for Applied Human Research (SCAHT)BaselSwitzerland
  4. 4.Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique UMR7104, Institut National de la Santé et de la Recherche MédicaleIllkirchFrance
  5. 5.Research Programs Unit, Molecular Neurology, Faculty of MedicineUniversity of HelsinkiHelsinkiFinland

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