title: Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle.
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.
authors.affiliation: 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.
authors.forename: Eija
authors.initials: E
authors.lastname: Pirinen
authors.affiliation: Nestlé Institute of Health Sciences, EPFL Innovation Park, Bâtiment G, CH-1015 Lausanne, Switzerland. Electronic address: carlos.cantoalvarez@rd.nestle.com.
authors.forename: Carles
authors.initials: C
authors.lastname: Cantó
authors.affiliation: Laboratory for Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Station 15, CH-1015 Lausanne, Switzerland.
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Jo
authors.affiliation: 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.
authors.forename: Laia
authors.initials: L
authors.lastname: Morato
authors.affiliation: Laboratory for Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Station 15, CH-1015 Lausanne, Switzerland.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Laboratory for Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Station 15, CH-1015 Lausanne, Switzerland.
authors.forename: Keir J
authors.initials: KJ
authors.lastname: Menzies
authors.affiliation: Laboratory for Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Station 15, CH-1015 Lausanne, Switzerland.
authors.forename: Evan G
authors.initials: EG
authors.lastname: Williams
authors.affiliation: Laboratory for Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Station 15, CH-1015 Lausanne, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mouchiroud
authors.affiliation: Laboratory for Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Station 15, CH-1015 Lausanne, Switzerland.
authors.forename: Norman
authors.initials: N
authors.lastname: Moullan
authors.affiliation: 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.
authors.forename: Carolina
authors.initials: C
authors.lastname: Hagberg
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Silvie
authors.initials: S
authors.lastname: Timmers
authors.affiliation: Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
authors.forename: Ralph
authors.initials: R
authors.lastname: Imhof
authors.affiliation: 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.
authors.forename: Jef
authors.initials: J
authors.lastname: Verbeek
authors.affiliation: 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.
authors.forename: Aurora
authors.initials: A
authors.lastname: Pujol
authors.affiliation: Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: van Loon
authors.affiliation: 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.
authors.forename: Carlo
authors.initials: C
authors.lastname: Viscomi
authors.affiliation: 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.
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.affiliation: Department of Human Biology, School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, 6200 MD Maastricht, The Netherlands.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schrauwen
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Sauve
authors.affiliation: Metabolic Signaling, École Polytechnique Fédérale de Lausanne, Station 15, CH-1015 Lausanne, Switzerland.
authors.forename: Kristina
authors.initials: K
authors.lastname: Schoonjans
authors.affiliation: Laboratory for Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Station 15, CH-1015 Lausanne, Switzerland. Electronic address: admin.auwerx@epfl.ch.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D017173:Caenorhabditis elegans; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D001549:Benzamides; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; C090712:iniparib; D011065:Poly(ADP-ribose) Polymerases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; C531550:olaparib