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

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. Payne, Matthew D. Hirschey

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish (US)
JournalJCI insight
Volume2
Issue number14
DOIs
StatePublished - Jul 20 2017

Fingerprint

Sirtuin 3
Nicotinamide Mononucleotide
Friedreich Ataxia
Cardiomyopathies
Energy Metabolism
NAD
Therapeutics
Mitochondrial Proteins

Keywords

  • Cardiology
  • Metabolism

Cite this

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich's ataxia cardiomyopathy model. / Martin, Angelical S.; Abraham, Dennis M.; Hershberger, Kathleen A.; Bhatt, Dhaval P.; Mao, Lan; Cui, Huaxia; Liu, Juan; Liu, Xiaojing; Muehlbauer, Michael J.; Grimsrud, Paul A.; Locasale, Jason W.; Payne, R.; Hirschey, Matthew D.

In: JCI insight, Vol. 2, No. 14, 20.07.2017.

Research output: Contribution to journalArticle

Martin, AS, Abraham, DM, Hershberger, KA, Bhatt, DP, Mao, L, Cui, H, Liu, J, Liu, X, Muehlbauer, MJ, Grimsrud, PA, Locasale, JW, Payne, R & Hirschey, MD 2017, 'Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich's ataxia cardiomyopathy model', JCI insight, vol. 2, no. 14. https://doi.org/10.1172/jci.insight.93885
Martin, Angelical S. ; Abraham, Dennis M. ; Hershberger, Kathleen A. ; Bhatt, Dhaval P. ; Mao, Lan ; Cui, Huaxia ; Liu, Juan ; Liu, Xiaojing ; Muehlbauer, Michael J. ; Grimsrud, Paul A. ; Locasale, Jason W. ; Payne, R. ; Hirschey, Matthew D. / Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich's ataxia cardiomyopathy model. In: JCI insight. 2017 ; Vol. 2, No. 14.
@article{2e75227007c84dd4b6af7f1caddee266,
title = "Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich's ataxia cardiomyopathy model",
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.",
keywords = "Cardiology, Metabolism",
author = "Martin, {Angelical S.} and Abraham, {Dennis M.} and Hershberger, {Kathleen A.} and Bhatt, {Dhaval P.} and Lan Mao and Huaxia Cui and Juan Liu and Xiaojing Liu and Muehlbauer, {Michael J.} and Grimsrud, {Paul A.} and Locasale, {Jason W.} and R. Payne and Hirschey, {Matthew D.}",
year = "2017",
month = "7",
day = "20",
doi = "10.1172/jci.insight.93885",
language = "English (US)",
volume = "2",
journal = "JCI insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "14",

}

TY - JOUR

T1 - Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich's ataxia cardiomyopathy model

AU - Martin, Angelical S.

AU - Abraham, Dennis M.

AU - Hershberger, Kathleen A.

AU - Bhatt, Dhaval P.

AU - Mao, Lan

AU - Cui, Huaxia

AU - Liu, Juan

AU - Liu, Xiaojing

AU - Muehlbauer, Michael J.

AU - Grimsrud, Paul A.

AU - Locasale, Jason W.

AU - Payne, R.

AU - Hirschey, Matthew D.

PY - 2017/7/20

Y1 - 2017/7/20

N2 - 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.

AB - 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.

KW - Cardiology

KW - Metabolism

UR - http://www.scopus.com/inward/record.url?scp=85049521649&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85049521649&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.93885

DO - 10.1172/jci.insight.93885

M3 - Article

C2 - 28724806

AN - SCOPUS:85049521649

VL - 2

JO - JCI insight

JF - JCI insight

SN - 2379-3708

IS - 14

ER -