Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model
Angelical S. Martin, … , R. Mark Payne, Matthew D. Hirschey
Angelical S. Martin, … , R. Mark Payne, Matthew D. Hirschey
Published July 20, 2017
Citation Information: JCI Insight. 2017;2(14):e93885. https://doi.org/10.1172/jci.insight.93885.
View: Text | PDF
Research Article Cardiology Metabolism

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model

  • Text
  • PDF
Abstract

Increasing NAD+ levels by supplementing with the precursor nicotinamide mononucleotide (NMN) improves cardiac function in multiple mouse models of disease. While NMN influences several aspects of mitochondrial metabolism, the molecular mechanisms by which increased NAD+ enhances cardiac function are poorly understood. A putative mechanism of NAD+ therapeutic action exists via activation of the mitochondrial NAD+-dependent protein deacetylase sirtuin 3 (SIRT3). We assessed the therapeutic efficacy of NMN and the role of SIRT3 in the Friedreich’s ataxia cardiomyopathy mouse model (FXN-KO). At baseline, the FXN-KO heart has mitochondrial protein hyperacetylation, reduced Sirt3 mRNA expression, and evidence of increased NAD+ salvage. Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels. To determine whether SIRT3 is required for NMN therapeutic efficacy, we generated SIRT3-KO and SIRT3-KO/FXN-KO (double KO [dKO]) models. The improvement in cardiac function upon NMN treatment in the FXN-KO is lost in the dKO model, demonstrating that the effects of NMN are dependent upon cardiac SIRT3. Coupled with cardio-protection, SIRT3 mediates NMN-induced improvements in both cardiac and extracardiac metabolic function and energy metabolism. Taken together, these results serve as important preclinical data for NMN supplementation or SIRT3 activator therapy in Friedreich’s ataxia patients.

Authors

Angelical S. Martin, Dennis M. Abraham, Kathleen A. Hershberger, Dhaval P. Bhatt, Lan Mao, Huaxia Cui, Juan Liu, Xiaojing Liu, Michael J. Muehlbauer, Paul A. Grimsrud, Jason W. Locasale, R. Mark Payne, Matthew D. Hirschey

×

Figure 3

NMN in the FXN-KO improves diastolic and normalizes systolic function in a SIRT3-dependent manner.

Options: View larger image (or click on image) Download as PowerPoint
NMN in the FXN-KO improves diastolic and normalizes systolic function in...
(A) Experimental schedule of treatment and clinical phenotyping protocols. E, echocardiography; C, noninvasive monitoring by CLAMS; P, PV-loop analysis; and †, sacrifice and collection of tissues for further analysis. Terminal procedures represented by olive-colored box. (B) Metabolomics profiling of cardiac NAD+ levels. Values are means ± SEM (n = 3–5 mice/group). (C) Wall thickness in NMN-treated animals measured via echocardiography at 9–10 weeks of age. Values are means ± SEM (n = 7–12 mice/group). (D–F) Hemodynamic measures assessed by PV-loop analysis: ejection fraction (D), active relaxation (τ, E), passive filling (linear end diastolic pressure volume relation [EDPVR], F), and contractility (linear ESPVR, G; dP/dtmax vs. end-diastolic volume [EDV], H; maximal elastance [Emax], I). Values are means ± SEM (E and G–I, n = 5–10 mice/group; D and F, n = 7–10 mice/group). Hashed line at 50% represents normal mouse ejection fraction. *P < 0.05, difference from saline-treated WT as determined by two-way ANOVA for 8 groups (4 genotypes, 2 treatment) and Bonferroni correction. W, WT; F, FXN-KO; S, SIRT3-KO; D, dKO; subscript S, saline; and subscript N, nicotinamide mononucleotide (NMN).

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts