Panajatovic 2017 IOC124

Role of PGC-1α associated mitochondrial biogenesis in statin-induced myotoxicity.

Link: Mitochondr Physiol Network 22.07

Panajatovic M, Singh F, Kraehenbuehl S, Bouitbir J (2017)

Event: IOC124

Statins are efficient medications used to lower cholesterol plasmatic levels that are generally well-tolerated, but can sometimes be associated with myopathy. We showed in a previous publication that statins impair the expression of PGC-1α in human and rat skeletal muscle, suggesting a role of PGC-1α in statin-induced muscle damage [1,2]. The purpose of this study was to investigate the effect of simvastatin on various physiological parameters in differentially expressed PGC-1α mouse models.

To test our hypothesis, we used 3 mouse models: mutant mice with muscle PGC-1α knockout (MKO), mutant mice overexpressing PGC-1α (MCK), and wild-type (WT) mice from both aforementioned mouse lines. We treated them for 3 weeks with water or simvastatin (5 mg/kg/d) by oral gavage. We performed a grip test and an air controlled treadmill to test their physical performance and exercise metabolism. Glucose homeostasis was assessed with glucose tolerance test. At the end the study, mice were sacrificed for blood and muscle collection (glycolytic gastrocnemius and oxidative soleus muscles) from which we used permeabilized fibres to measure mitochondrial respiration using the O2k-FluoRespirometer (Oroboros), simultaneously measuring H₂O₂ production fluorometrically in order to assess the free radical leak.

Simvastatin showed increased impairment in wild-type mice, manifested by decreased exercise capacity, and glucose intolerance. Moreover, we showed in permeabilized fibers that complex I and II of the electron transport chain were inhibited by simvastatin in the glycolytic gastrocnemius muscle whereas the oxidative soleus muscle was unaffected. Mitochondrial H₂O₂ production was increased only in gastrocnemius from the simvastatin treated mice. In PGC-1α knockout mice, the treatment with simvastatin decreased exercise capacity as found in wild-type mice. Furthermore, in the simvastatin treated knockout mice, we found an inhibition of complex I of the electron transport chain in gastrocnemius and of unexpectedly complex II in soleus. Finally, PGC-1α overexpressing mice seemed to mitigate simvastatin myotoxic effects on exercise and mitochondrial function.

PGC-1α seems to be a susceptibility factor in simvastatin induced myotoxicity. While the extent of simvastatin myotoxicity in WT mice was as expected only in glycolytic muscle, the mitochondrial function and physical performance were not affected in PGC-1α overexpressing mice. In contrast, PGC-1α knockout mice showed increased impairment of their physical performance and mitochondrial dysfunction in glycolytic and oxidative muscles. Further analysis are planned to better understand the mechanisms underlying simvastatin-induced myotoxicity.

• Bioblast editor: Beno M, Kandolf G • O2k-Network Lab: CH Basel Kraehenbuehl S, FR Strasbourg Zoll J

Labels: MiParea: Respiration, Genetic knockout;overexpression, Exercise physiology;nutrition;life style, Pharmacology;toxicology  Pathology: Myopathy 

Organism: Mouse  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue 

Pathway: N, S, NS  HRR: Oxygraph-2k, O2k-Fluorometer 

References

1. Bouitbir J, Charles AL, Echaniz-Laguna A, Kindo M, Daussin F, Auwerx J, Piquard F, Geny B, Zoll J (2012) Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a 'mitohormesis' mechanism involving reactive oxygen species and PGC-1. Europ Heart J 33:1397-1407.
2. Bouitbir J, Singh F, Charles AL, Schlagowski AI, Bonifacio A, Echaniz-Laguna A, Geny B, Krahenbuhl S, Zoll J (2016) Statins trigger mitochondrial reactive oxygen species-induced apoptosis in glycolytic skeletal muscle. Antioxid Redox Signal 24:84-98.

Affiliations

Clinical Pharmacology & Toxicology, Univ Hospital, 4031 Basel, Switzerland. -