Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a 'mitohormesis' mechanism involving reactive oxygen species and PGC-1

Statins protect against cardiovascular-related mortality but induce skeletal muscle toxicity. To investigate mechanisms of statins, we tested the hypothesis that statins optimized cardiac mitochondrial function but impaired vulnerable skeletal muscle by inducing different level of reactive oxygen sp...

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Vydané v:European heart journal Ročník 33; číslo 11; s. 1397
Hlavní autori: Bouitbir, Jamal, Charles, Anne-Laure, Echaniz-Laguna, Andoni, Kindo, Michel, Daussin, Frédéric, Auwerx, Johan, Piquard, François, Geny, Bernard, Zoll, Joffrey
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: England 01.06.2012
Predmet:
Animals
Antioxidants - pharmacology
Atorvastatin Calcium
Heart Atria
Heptanoic Acids - pharmacology
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology
Male
Mitochondria, Heart - drug effects
Mitochondria, Muscle - drug effects
Muscle Fibers, Skeletal - drug effects
Muscle Fibers, Skeletal - metabolism
Muscle, Skeletal - drug effects
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - metabolism
Pyrroles - pharmacology
Quercetin - pharmacology
Rats
Rats, Wistar
Reactive Oxygen Species - metabolism
RNA, Messenger - metabolism
Superoxide Dismutase - pharmacology
Transcription Factors - metabolism
ISSN:1522-9645, 1522-9645
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Shrnutí:Statins protect against cardiovascular-related mortality but induce skeletal muscle toxicity. To investigate mechanisms of statins, we tested the hypothesis that statins optimized cardiac mitochondrial function but impaired vulnerable skeletal muscle by inducing different level of reactive oxygen species (ROS). In atrium of patients treated with statins, ROS production was decreased and oxidative capacities were enhanced together with an extensive augmentation of mRNAs expression of peroxisome proliferator-activated receptor gamma co-activator (PGC-1) family. However, in deltoid biopsies from patients with statin-induced muscular myopathy, oxidative capacities were decreased together with ROS increase and a collapse of PGC-1 mRNA expression. Several animal and cell culture experiments were conducted and showed by using ROS scavengers that ROS production was the triggering factor responsible of atorvastatin-induced activation of mitochondrial biogenesis pathway and improvement of antioxidant capacities in heart. Conversely, in skeletal muscle, the large augmentation of ROS production following treatment induced mitochondrial impairments, and reduced mitochondrial biogenesis mechanisms. Quercetin, an antioxidant molecule, was able to counteract skeletal muscle deleterious effects of atorvastatin in rat. Our findings identify statins as a new activating factor of cardiac mitochondrial biogenesis and antioxidant capacities, and suggest the importance of ROS/PGC-1 signalling pathway as a key element in regulation of mitochondrial function in cardiac as well as skeletal muscles.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:1522-9645
1522-9645
DOI:10.1093/eurheartj/ehr224