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PGC-1α plays a pivotal role in simvastatin-induced exercise impairment in mice
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 4602367
Author(s) Panajatovic, Miljenko Valentin; Singh, François; Roos, Noëmi Johanna; Duthaler, Urs; Handschin, Christoph; Krähenbühl, Stephan; Bouitbir, Jamal
Author(s) at UniBasel Bouitbir, Jamal
Panajatovic, Miljenko
Singh, François
Roos, Noëmi Johanna
Duthaler, Urs
Krähenbühl, Stephan
Handschin, Christoph
Year 2020
Title PGC-1α plays a pivotal role in simvastatin-induced exercise impairment in mice
Journal Acta physiologica (Oxford, England)
Volume 228
Number 4
Pages / Article-Number e13402
Keywords PGC-1α; exercise capacity; grip strength; mitochondria; reactive oxygen species; statins
Mesh terms Animals; Citrate (si)-Synthase, metabolism; DNA, Mitochondrial, metabolism; Glutathione, metabolism; Glycolysis, drug effects; Hydrogen Peroxide, metabolism; Hydroxymethylglutaryl-CoA Reductase Inhibitors, adverse effects; Lactic Acid, blood; Mice; Mice, Knockout; Mitochondria, Muscle, pathology; Muscle, Skeletal, metabolism; Myotoxicity, metabolism; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, metabolism; Physical Conditioning, Animal, physiology; Simvastatin, adverse effects
Abstract Statins decrease cardiovascular complications, but can induce myopathy. Here, we explored the implication of PGC-1α in statin-associated myotoxicity.; We treated PGC-1α knockout (KO), PGC-1α overexpression (OE) and wild-type (WT) mice orally with 5 mg simvastatin kg; -1; day; -1; for 3 weeks and assessed muscle function and metabolism.; In WT and KO mice, but not in OE mice, simvastatin decreased grip strength, maximal running distance and vertical power assessed by ergometry. Post-exercise plasma lactate concentrations were higher in WT and KO compared to OE mice. In glycolytic gastrocnemius, simvastatin decreased mitochondrial respiration, increased mitochondrial ROS production and free radical leak in WT and KO, but not in OE mice. Simvastatin increased mRNA expression of Sod1 and Sod2 in glycolytic and oxidative gastrocnemius of WT, but decreased it in KO mice. OE mice had a higher mitochondrial DNA content in both gastrocnemius than WT or KO mice and simvastatin exhibited a trend to decrease the citrate synthase activity in white and red gastrocnemius in all treatment groups. Simvastatin showed a trend to decrease the mitochondrial volume fraction in both muscle types of all treatment groups. Mitochondria were smaller in WT and KO compared to OE mice and simvastatin further reduced the mitochondrial size in WT and KO mice, but not in OE mice.; Simvastatin impairs skeletal muscle function, muscle oxidative metabolism and mitochondrial morphology preferentially in WT and KO mice, whereas OE mice appear to be protected, suggesting a role of PGC-1α in preventing simvastatin-associated myotoxicity.
Publisher John Wiley & Sons
ISSN/ISBN 1748-1708 ; 1748-1716
URL https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7100017/
edoc-URL https://edoc.unibas.ch/78280/
Full Text on edoc Available
Digital Object Identifier DOI 10.1111/apha.13402
PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/31605661
Document type (ISI) Journal Article
 
   

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