Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle

• Published in: Cell metabolism Vol. 19; no. 6; pp. 1034 - 1041
• Main Authors: Pirinen, Eija, Cantó, Carles, Jo, Young Suk, Morato, Laia, Zhang, Hongbo, Menzies, Keir J., Williams, Evan G., 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03-06-2014
• Subjects: Animals; Benzamides - pharmacology; Benzimidazoles - pharmacology; Caenorhabditis elegans; Cells, Cultured; Energy Metabolism - physiology; Enzyme Inhibitors - pharmacology; Humans; Male; Medicin och hälsovetenskap; 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; Poly(ADP-ribose) Polymerases - metabolism; Sirtuin 1 - genetics; Sirtuin 1 - metabolism
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2014.04.002

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.
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•Inhibition of poly(ADP-ribose) polymerases (PARPs) enhances endurance performance•Inhibition of PARPs improves mitochondrial function in skeletal muscle•Parp-1 correlates with energy expenditure in heterogeneous mouse populations•Genetic and acquired mitochondrial defects can be rescued by PARP inhibition
Pirinen et al. show that long-term pharmacological poly(ADP-ribose) polymerase (PARP) inhibition enhances muscle mitochondrial function and fitness in mice. PARP inhibitors also improve genetic or acquired mitochondrial dysfunction in worms and human cells, highlighting their therapeutic use for muscle dysfunction associated with defective mitochondrial function.