Alternative NAD+ biosynthesis pathway activated by energy stress stimulates glycolysis in cardiac cells - 26/03/18
Résumé |
Introduction |
NAD+ is a key co-enzyme in energy metabolism and a signaling substrate used by the sirtuins and poly (ADPribose) polymerases (PARPs), regulating energy metabolism and oxidative stress response. Myocardial NAD+ levels are reduced in various mouse models of heart failure in association with the repression of the NAMPT, a major enzyme that recycle the nicotinamide (NAM) produced by sirtuins and PARPs to regenerate NAD+ pools.
Objective |
We aim to understand the metabolism of nicotinamide riboside (NR), an alternative vitamin B3 precursor of NAD+ used by NMRK kinases, to restore NAD+ levels, and its effects on energy metabolism in cardiac cells.
Method |
We treated neonatal (NRC) and adult rat cardiomyocytes (ARC) with FK866 to inhibit NAMPT and evaluated the impact on NAD+ level and gene expression. We evaluated the ability of NR to sustain NAD+ synthesis when NAMPT is repressed and its impact on NRC metabolism using the Seahorse cell analyzer and carbohydrate metabolic tracing.
Results |
We show in NRC and ARC that FK866 treatment depletes NAD+ levels and triggers a robust induction of the Nmrk2 kinase; NR supplementation is able to maintain the NAD+ to normal level despite the inhibition of NAMPT. We also found in NRC that the Nmrk2 gene expression was responsive to AMPK energy stress sensor pathway via PPARα activation. We showed that NR alone is able to stimulate energy metabolism by specifically increasing glycolysis but not mitochondrial respiration in NRC. 13C-Glucose tracing data are currently generated to better understand the impact of NR on glycolysis in cardiac cells.
Conclusion |
NR supplementation represents an efficient alternative to NAM to sustain NAD+ levels in cardiac cells in conditions of energetic stress when NAMPT enzyme is repressed. Its ability to specifically stimulate glycolysis suggests that the Nmrk2 kinase could be locally associated with glycolytic complexes, which is a hypothesis under current investigation.
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Vol 10 - N° 2
P. 229 - avril 2018 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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