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

TitlePharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle.
Publication TypeJournal Article
Year of Publication2014
AuthorsPirinen, E, Cantó, C, Jo, YSuk, Morato, L, Zhang, H, Menzies, KJ, Williams, EG, Mouchiroud, L, Moullan, N, Hagberg, C, Li, W, Timmers, S, Imhof, R, Verbeek, J, Pujol, A, van Loon, B, Viscomi, C, Zeviani, M, Schrauwen, P, Sauve, AA, Schoonjans, K, Auwerx, J
JournalCell Metab
Date Published2014 Jun 03
KeywordsAnimals, Benzamides, Benzimidazoles, Caenorhabditis elegans, Cells, Cultured, Energy Metabolism, Enzyme Inhibitors, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Muscle Fibers, Skeletal, Obesity, Phthalazines, Piperazines, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases, Sirtuin 1

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.

Alternate JournalCell Metab.
Citation Key10.1016/j.cmet.2014.04.002
PubMed ID24814482
PubMed Central IDPMC4047186
Grant ListMC_UP_1002/1 / / Medical Research Council / United Kingdom
R01 AG043930 / AG / NIA NIH HHS / United States
R01 HL106511 / HL / NHLBI NIH HHS / United States
R01 GM106072 / GM / NIGMS NIH HHS / United States
R01HL106511-01A / HL / NHLBI NIH HHS / United States
R01AG043930 / AG / NIA NIH HHS / United States