Unravelling the PARamount role of NAD+-metabolism and PARylation in skeletal muscle and satellite cell health

Description

Abstract Poly-ADP-Ribose Polymerases (PARPs) are a family of proteins that consume nicotinamide adenine dinucleotide (NAD+; a form of Vitamin B3) to modify proteins in a process called Poly-ADPribosylation or PARylation. Specifically, PARPs covalently attach NAD+-derived ADP-ribose groups to proteins that can then be removed by PAR glycohydrolase (PARG). PARylation signalling was identified as a cellular response to genotoxic stressors with its primary role in the DNA repair process, but has now been associated with glycolysis, chromatin modulation, differentiation, methylation and replication. Our previous work demonstrated that NAD+ availability is critical for maintaining muscle health. In particular, we showed that reduced MuSC function in aged mice is associated with reduced NAD+ levels and treatment with the NAD+ precursor nicotinamide riboside rejuvenated MuSCs and improved their capacity for muscle regeneration. We have also shown that NAD+-levels are limited in the muscle of mouse models of muscular dystrophy as a result of elevated PARylation signalling. Given the surge in use and development of pharmaceuticals that alter NAD+-homeostasis and PARylation status, we set out to examine the physiological relevance of these changes in muscle during health, disease and regeneration.

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