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. Mark Payne, and Matthew D. Hirschey, JCI Insight. 2017;2(14):e93885. doi: 10.1172/jci.insight.93885.

Increasing NAD+ levels by supplementing with the precursor nicotinamide mononucleotide (NMN) improves cardiac function in multiple mouse models of disease. 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. Our data define a clear role for SIRT3 in mediating the beneficial effects of NMN in this HF model; thus, future studies in the FXN-KO and dKO models would be of interest to evaluate the consequences of manipulating of redox-induced acetylation versus SIRT3-regulated acetylation. These studies include studies dedicated to varying the NMN dosing regimen, as well as acetyl-proteomic analysis of hearts from these NMN-treated mice. Our findings presented here serve as important preclinical data to highlight NMN supplementation and/or SIRT3 agonist treatment as potential therapeutic strategies in FRDA patients and HF.

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