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

Authors
 Eija Pirinen  ;  Carles Canto  ;  Young Suk Jo  ;  Laia Morato  ;  Hongbo Zhang  ;  Keir 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 Sauve  ;  Kristina Schoonjans  ;  Johan Auwerx 
Citation
 CELL METABOLISM, Vol.19(6) : 1034-1041, 2014 
Journal Title
 CELL METABOLISM 
ISSN
 1550-4131 
Issue Date
2014
MeSH
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 ; Poly(ADP-ribose) Polymerases/metabolism* ; Sirtuin 1/genetics ; Sirtuin 1/metabolism
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.
Files in This Item:
T201406183.pdf Download
DOI
10.1016/j.cmet.2014.04.002
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Jo, Young Suk(조영석) ORCID logo https://orcid.org/0000-0001-9926-8389
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/139077
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