Nicotinamide mononucleotide preserves mitochondrial function and increases survival in hemorrhagic shock
Carrie A. Sims, … , Antonio Davila Jr., Joseph A. Baur
Carrie A. Sims, … , Antonio Davila Jr., Joseph A. Baur
Published September 6, 2018
Citation Information: JCI Insight. 2018;3(17):e120182. https://doi.org/10.1172/jci.insight.120182.
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Research Article Inflammation Metabolism

Nicotinamide mononucleotide preserves mitochondrial function and increases survival in hemorrhagic shock

Abstract

Hemorrhagic shock depletes nicotinamide adenine dinucleotide (NAD) and causes metabolic derangements that, in severe cases, cannot be overcome, even after restoration of blood volume and pressure. However, current strategies to treat acute blood loss do not target cellular metabolism. We hypothesized that supplemental nicotinamide mononucleotide (NMN), the immediate biosynthetic precursor to NAD, would support cellular energetics and enhance physiologic resilience to hemorrhagic shock. In a rodent model of decompensated hemorrhagic shock, rats receiving NMN displayed significantly reduced lactic acidosis and serum IL-6 levels, two strong predictors of mortality in human patients. In both livers and kidneys, NMN increased NAD levels and prevented mitochondrial dysfunction. Moreover, NMN preserved mitochondrial function in isolated hepatocytes cocultured with proinflammatory cytokines, indicating a cell-autonomous protective effect that is independent from the reduction in circulating IL-6. In kidneys, but not in livers, NMN was sufficient to prevent ATP loss following shock and resuscitation. Overall, NMN increased the time animals could sustain severe shock before requiring resuscitation by nearly 25% and significantly improved survival after resuscitation (P = 0.018), whether NMN was given as a pretreatment or only as an adjunct during resuscitation. Thus, we demonstrate that NMN substantially mitigates inflammation, improves cellular metabolism, and promotes survival following hemorrhagic shock.

Authors

Carrie A. Sims, Yuxia Guan, Sarmistha Mukherjee, Khushboo Singh, Paul Botolin, Antonio Davila Jr., Joseph A. Baur

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Figure 7

NMN enhances tolerance to hemorrhagic shock.

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NMN enhances tolerance to hemorrhagic shock. Prior to the induction of h...
Prior to the induction of hemorrhagic shock, animals received regular water or water containing 400 mg/kg/d NMN for 5 days. All rats (n = 11/group) were then bled to a mean arterial blood pressure (MAP) of 40 mmHg and then maintained at 40 mmHg, with incremental fluid boluses until 40% of the shed blood volume had been returned. Animals pretreated with water were then resuscitated with 4 times the shed volume in lactated Ringer’s (Control) or lactated Ringer’s with 400 mg/kg NMN over 60 minutes (NMN PostTreatment). Animals pretreated with NMN in their drinking water were also resuscitated with 4 times the shed volume in lactated Ringer’s plus 400 mg/kg NMN over 60 minutes (NMN). All animals (Control, NMN, NMN PostTreatment) were then observed for 48 hours (A). Animals pretreated with NMN were able to sustain a shock state longer than controls before requiring resuscitation (B), despite a similar percentage of blood loss (C). As expected control animals and animals that received NMN only during resuscitation (NMN PostTreatment) were similar in terms of shock time and blood loss. NMN-pretreated animals had lower blood lactate concentrations following resuscitation than control animals (D). Whether NMN was given as both a pretreatment and a resuscitation adjunct (NMN) or only an adjunct during resuscitation (NMN PostTreatment), animals treated with NMN were significantly more likely to survive than were controls (E). When both NMN pretreatment and resuscitation-only strategies were combined, animals treated with NMN had a clear survival advantage when compared with control animals (F). Data are represented as mean ± SEM. One-way ANOVA was used to compare groups with a post hoc 2-tailed Student’s t or Mann-Whitney test if statistically significant. Survival was analyzed using Kaplan-Meier curves with a log-rank Mantel-Cox test. *P < 0.05.