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

Eija Pirinen, Carles Cantó, Young Suk Jo, Laia Morato, Hongbo Zhang, Keir J. Menzies, Evan G. Williams, Laurent Mouchiroud, Norman Moullan, Carolina Hagberg, Wei Li, Silvie Timmers, Ralph Imhof, Jef Verbeek, Aurora Pujol, Barbara Van Loon, Carlo Viscomi, Massimo Zeviani, Patrick Schrauwen, Anthony A. SauveKristina Schoonjans, Johan Auwerx

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1034-1041
Number of pages8
JournalCell Metabolism
Volume19
Issue number6
DOIs
Publication statusPublished - Jun 3 2014

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

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  • Cite this

    Pirinen, E., Cantó, C., Jo, Y. S., Morato, L., Zhang, H., Menzies, K. J., Williams, E. G., 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., ... Auwerx, J. (2014). Pharmacological inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle. Cell Metabolism, 19(6), 1034-1041. https://doi.org/10.1016/j.cmet.2014.04.002