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Arch Toxicol. 2019 Feb;93(2):487-504. doi: 10.1007/s00204-018-2369-7. Epub 2018 Dec 3.

PGC-1β modulates statin-associated myotoxicity in mice.

Author information

1
Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital, Hebelstrasse 20, 4031, Basel, Switzerland.
2
Université de Strasbourg, Fédération de Médecine Translationnelle, Equipe d'Accueil 3072, Institut de Physiologie, Faculté de Médecine, Strasbourg, France.
3
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 Médicale, Illkirch, France.
4
Research Programs Unit, Molecular Neurology, Faculty of Medicine, University of Helsinki, 00290, Helsinki, Finland.
5
Swiss Centre for Applied Human Research (SCAHT), Basel, Switzerland.
6
Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital, Hebelstrasse 20, 4031, Basel, Switzerland. jamal.bouitbir@unibas.ch.
7
Swiss Centre for Applied Human Research (SCAHT), Basel, Switzerland. jamal.bouitbir@unibas.ch.

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.

KEYWORDS:

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

PMID:
30511338
DOI:
10.1007/s00204-018-2369-7

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