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Cell Metab. 2014 Jun 3;19(6):1034-41. doi: 10.1016/j.cmet.2014.04.002. Epub 2014 May 8.

Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle.

Author information

1
Laboratory for Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Station 15, CH-1015 Lausanne, Switzerland; Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, FI-70211 Kuopio, Finland; Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Haartmanninkatu 8, FI-00290, Helsinki, Finland.
2
Nestlé Institute of Health Sciences, EPFL Innovation Park, Bâtiment G, CH-1015 Lausanne, Switzerland. Electronic address: carlos.cantoalvarez@rd.nestle.com.
3
Laboratory for Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Station 15, CH-1015 Lausanne, Switzerland.
4
Laboratory for Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Station 15, CH-1015 Lausanne, Switzerland; Neurometabolic Diseases Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Catalan Institution of Research and Advanced Studies (ICREA), 08908 Barcelona, Catalonia, Spain; Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII U759, Spain.
5
Laboratory for Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Station 15, CH-1015 Lausanne, Switzerland; Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute, SE-17177 Stockholm, Sweden.
6
Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
7
Laboratory for Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Station 15, CH-1015 Lausanne, Switzerland; Department of Human Biology, School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, 6200 MD Maastricht, The Netherlands.
8
Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
9
Laboratory for Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Station 15, CH-1015 Lausanne, Switzerland; Department of Hepatology, University Hospital Leuven, 3000 Leuven, Belgium.
10
Neurometabolic Diseases Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Catalan Institution of Research and Advanced Studies (ICREA), 08908 Barcelona, Catalonia, Spain; Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII U759, Spain.
11
Medical Research Council, Mitochondrial Biology Unit, Cambridge CB2 0XY, UK; Unit of Molecular Neurogenetics, The Foundation "Carlo Besta" Institute of Neurology IRCCS, 20133 Milan, Italy.
12
Department of Human Biology, School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, 6200 MD Maastricht, The Netherlands.
13
Metabolic Signaling, École Polytechnique Fédérale de Lausanne, Station 15, CH-1015 Lausanne, Switzerland.
14
Laboratory for Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Station 15, CH-1015 Lausanne, Switzerland. Electronic address: admin.auwerx@epfl.ch.

Abstract

We previously demonstrated that the deletion of the poly(ADP-ribose)polymerase (Parp)-1 gene in mice enhances oxidative metabolism, thereby protecting against diet-induced obesity. However, the therapeutic use of PARP inhibitors to enhance mitochondrial function remains to be explored. Here, we show tight negative correlation between Parp-1 expression and energy expenditure in heterogeneous mouse populations, indicating that variations in PARP-1 activity have an impact on metabolic homeostasis. Notably, these genetic correlations can be translated into pharmacological applications. Long-term treatment with PARP inhibitors enhances fitness in mice by increasing the abundance of mitochondrial respiratory complexes and boosting mitochondrial respiratory capacity. Furthermore, PARP inhibitors reverse mitochondrial defects in primary myotubes of obese humans and attenuate genetic defects of mitochondrial metabolism in human fibroblasts and C. elegans. Overall, our work validates in worm, mouse, and human models that PARP inhibition may be used to treat both genetic and acquired muscle dysfunction linked to defective mitochondrial function.

Comment in

PMID:
24814482
PMCID:
PMC4047186
DOI:
10.1016/j.cmet.2014.04.002
[Indexed for MEDLINE]
Free PMC Article

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