Reference : Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitoc...
Scientific journals : Article
Life sciences : Genetics & genetic processes
Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle.
Pirinen, Eija [> >]
Canto, Carles [> >]
Jo, Young Suk [> >]
Morato, Laia [> >]
Zhang, Hongbo [> >]
Menzies, Keir J. [> >]
Williams, Evan mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
Mouchiroud, Laurent [> >]
Moullan, Norman [> >]
Hagberg, Carolina [> >]
Li, Wei [> >]
Timmers, Silvie [> >]
Imhof, Ralph [> >]
Verbeek, Jef [> >]
Pujol, Aurora [> >]
van Loon, Barbara [> >]
Viscomi, Carlo [> >]
Zeviani, Massimo [> >]
Schrauwen, Patrick [> >]
Sauve, Anthony A. [> >]
Schoonjans, Kristina [> >]
Auwerx, Johan [> >]
Cell metabolism
Yes (verified by ORBilu)
United States
[en] Animals ; Benzamides/pharmacology ; Benzimidazoles/pharmacology ; Caenorhabditis elegans ; Cells, Cultured ; Energy Metabolism/physiology ; Enzyme Inhibitors/pharmacology ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/metabolism ; Muscle Fibers, Skeletal/metabolism ; Obesity/metabolism ; Phthalazines/pharmacology ; Piperazines/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases/biosynthesis/metabolism ; Sirtuin 1/genetics/metabolism
[en] 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.
Copyright (c) 2014 Elsevier Inc. All rights reserved.

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