%0 Journal Article %A Sergiy M. Nadtochiy %A Yves T. Wang %A Keith Nehrke %A Joshua Munger %A Paul S. Brookes %T Nicotinamide mononucleotide (NMN) affords cardioprotection by stimulating glycolysis %D 2017 %R 10.1101/230938 %J bioRxiv %P 230938 %X Rationale: Nicotinamide adenine dinucleotide (NAD+) is a substrate for sirtuin (SIRT) lysine deacylases. Stimulation of SIRT1 is cardioprotective against ischemia-reperfusion (IR) injury, prompting interest in orally-available NAD+ precursors such as nicotinamide mononucleotide (NMN) as potential cardioprotective agents. While the biological activity of NMN has been largely attributed to SIRT stimulation, NMN effects on metabolism, and any role these may play in cardioprotection, are less well understood. Objective: To investigate potential non-SIRT mechanisms for NMN cardioprotection, with a focus on metabolism. Methods & Results: NMN was protective in perfused mouse hearts (post-IR functional recovery: NMN 42±7% vs. vehicle 11±3%). However, protection was insensitive to the SIRT1 inhibitor splitomicin (recovery 47±8%), and NMN did not impact lysine acetylation in the cytosol where cardiac SIRT1 is located, thus suggesting NMN does not stimulate cardiac SIRT1 activity. Surprisingly, NMN was not protective in hearts perfused without glucose (palmitate as fuel source; recovery 11±4%). Since glycolysis requires NAD+, and is associated with some cardioprotective paradigms, we hypothesized NMN protection may be due to glycolytic stimulation. In primary cardiomyocytes, NMN induced cytosolic and extracellular acidification, and enhanced lactate generation, indicative of increased glycolysis. Finally, since extension of ischemic acidosis into early reperfusion (i.e., acid post-conditioning) is cardioprotective, we hypothesized that NMN delivery at reperfusion may protect, and indeed this was the case (recovery 39±8%). Conclusions: The acute cardioprotective benefit of NMN is mediated via glycolytic stimulation, and this effect of NMN may be worthy of investigation in other situations where NAD+ precursor supplements are of therapeutic interest. %U https://www.biorxiv.org/content/biorxiv/early/2017/12/08/230938.full.pdf