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. 2022:2:887733.
doi: 10.3389/fmmed.2022.887733. Epub 2022 May 9.

Nicotinamide Riboside Improves Cardiac Function and Prolongs Survival After Disruption of the Cardiomyocyte Clock

Pieterjan Dierickx  1   2 , Bryce J Carpenter  1   2 , Isaac Celwyn  1   2 , Daniel P Kelly  1   3 , Joseph A Baur  1   4 , Mitchell A Lazar  1   2
Affiliations

Nicotinamide Riboside Improves Cardiac Function and Prolongs Survival After Disruption of the Cardiomyocyte Clock

Pieterjan Dierickx et al. Front Mol Med. 2022.

Abstract

The REV-ERB nuclear receptors are key components of the circadian clock. Loss of REV-ERBs in the mouse heart causes dilated cardiomyopathy and premature lethality. This is associated with a marked reduction in NAD+ production, but whether this plays a role in the pathophysiology of this heart failure model is not known. Here, we show that supplementation with the NAD+ precursor NR as a dietary supplement improves heart function and extends the lifespan of female mice lacking cardiac REV-ERBs. Thus, boosting NAD+ levels can improve cardiac function in a setting of heart failure caused by disruption of circadian clock factors, providing new insights into the links between the circadian clock, energy metabolism, and cardiac function.

Keywords: NAD+; cardiac metabolism; circadian clock; heart failure; nuclear hormone receptors.

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Conflict of interest statement

Conflict of Interest: ML receives research support from Pfizer for unrelated work, serves as an advisory board member for Pfizer and Flare Therapeutics, has consulted for Novartis, Madrigal, and Calico and Third Rock, and holds equity in KDAC Therapeutics and Flare Therapeutics. DK serves as an advisory board member for Pfizer and Amgen. JB is an inventor on a patent for using NAD+ precursors in liver injury, is a consultant for Pfizer and Cytokinetics, and has received research funding and materials from Elysium Health and Metro International Biotech, both of which have an interest in NAD+ precursors. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
NR supplementation strategy to bypass low cardiac Nampt levels. (A) Relative Nampt and (B) Nmrk2 mRNA expression in hearts from 2-month-old female αMHC-Cre+ Rev-erbα/β double floxed (CM-RevDKO) vs littermate controls (αMHC-Cre- Rev-erbα/β double floxed) (n = 3 hearts/genotype/timepoint; ***p < 0.001 by two-way ANOVA). (C) Schematic representation of NAD+ boosting strategy in CM-RevDKO mice with NR.
FIGURE 2
FIGURE 2
NAD+ levels after 1-month NR treatment and its long-term effect on body weight and composition. (A) Schematic representing NR treatment and NAD+ concentration in livers and hearts of control versus CM-RevDKO female mice treated with NR versus H2O (control) for 1 month (n = 4–6/genotype/treatment). (B) mRNA expression in hearts from 2-month- and 6-month-old female CM-RevDKO vs controls (n = 3–6 hearts/genotype; ns, not significant; *p < 0.05, **p < 0.01, ****p < 0.0001 by one-way ANOVA, followed by a Šidák’s multiple comparisons test). (C) Schematic representing NR treatment and body weight and (D) body composition of female control vs CM-RevDKO mice treated with NR for 4 months, starting at an age of 2 months (n = 4–7/genotype/treatment).
FIGURE 3
FIGURE 3
NR supplementation alleviates cardiac stress and improves heart function in female CM-RevDKO mice. (A) Schematic representing NR treatment and relative Nppb and (B) Nppa mRNA expression in hearts from 3-month-old female CM-RevDKO vs controls treated with NR for 1 month (n = 4–6 hearts/genotype/treatment). (C) Biventricular to body weight (BVW/BW) ratio from mice in (A,B). (D) mRNA expression in hearts from 3-month-old female CM-RevDKO vs controls treated with NR for 1 month (n = 4–6 hearts/genotype/treatment; ns, not significant; *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001 by one-way ANOVA, followed by a Šidák’s multiple comparisons test). (E) Schematic representing NR treatment and cardiac function: EF: Left ventricular ejection (%) fraction data determined by echocardiagraphy for 6–7-month-old female mice and (right) representative short axis M-mode images from echocardiography on mice from the (left). (n = 6–9/condition; 2 CM-RevDKO animals on H2O (control) died before they could be echoed; ns, not significant; **p < 0.01; ****p < 0.0001 by 2-sided Student’s t test.
FIGURE 4
FIGURE 4
NR supplementation extends median lifespan of female CM-RevDKO mice. (A) Schematic representing NR treatment and Kaplan-Meier survival curves for control and CM-RevDKO female mice treated without (H2O) or with NR (n = 6–7/condition). *p < 0.05 by log-rank (Mantel-Cox) test.
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