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Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a 'mitohormesis' mechanism involving reactive oxygen species and PGC-1.
Eur Heart J. 2012 Jun; 33(11):1397-407.EH

Abstract

AIMS

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).

METHODS AND RESULTS

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.

CONCLUSION

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.

Authors+Show Affiliations

Faculty of Medicine, University of Strasbourg, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21775390

Citation

Bouitbir, Jamal, et al. "Opposite Effects of Statins On Mitochondria of Cardiac and Skeletal Muscles: a 'mitohormesis' Mechanism Involving Reactive Oxygen Species and PGC-1." European Heart Journal, vol. 33, no. 11, 2012, pp. 1397-407.
Bouitbir J, Charles AL, Echaniz-Laguna A, et al. Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a 'mitohormesis' mechanism involving reactive oxygen species and PGC-1. Eur Heart J. 2012;33(11):1397-407.
Bouitbir, J., Charles, A. L., 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. European Heart Journal, 33(11), 1397-407. https://doi.org/10.1093/eurheartj/ehr224
Bouitbir J, et al. Opposite Effects of Statins On Mitochondria of Cardiac and Skeletal Muscles: a 'mitohormesis' Mechanism Involving Reactive Oxygen Species and PGC-1. Eur Heart J. 2012;33(11):1397-407. PubMed PMID: 21775390.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a 'mitohormesis' mechanism involving reactive oxygen species and PGC-1. AU - Bouitbir,Jamal, AU - Charles,Anne-Laure, AU - Echaniz-Laguna,Andoni, AU - Kindo,Michel, AU - Daussin,Frédéric, AU - Auwerx,Johan, AU - Piquard,François, AU - Geny,Bernard, AU - Zoll,Joffrey, Y1 - 2011/07/20/ PY - 2011/7/22/entrez PY - 2011/7/22/pubmed PY - 2012/8/28/medline SP - 1397 EP - 407 JF - European heart journal JO - Eur Heart J VL - 33 IS - 11 N2 - AIMS: 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). METHODS AND RESULTS: 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. CONCLUSION: 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. SN - 1522-9645 UR - https://www.unboundmedicine.com/medline/citation/21775390/Opposite_effects_of_statins_on_mitochondria_of_cardiac_and_skeletal_muscles:_a_'mitohormesis'_mechanism_involving_reactive_oxygen_species_and_PGC_1_ L2 - https://academic.oup.com/eurheartj/article-lookup/doi/10.1093/eurheartj/ehr224 DB - PRIME DP - Unbound Medicine ER -