Angelical S. Martin1,2, Dennis M. Abraham3, Kathleen A. Hershberger1,2, Lan Mao3, Huaxia Cui1, Juan Liu2, Xiaojing Liu2, Michael J. Muehlbauer1, Jason W. Locasale1,2, R. Mark Payne4, and Matthew D. Hirschey1,2,5
1Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Durham, NC
2Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC
3Department of Medicine, Division of Cardiology and Duke Cardiovascular Physiology Core, Duke University Medical Center, Durham, NC
4Department of Medicine, Division of Pediatrics, Indiana University, Indianapolis, IN
5Department of Medicine, Division of Endocrinology, Metabolism, & Nutrition, Duke University Medical Center, Durham, NC
Hypertrophic cardiomyopathy and heart failure are common human pathologies stemming from inborn errors in fatty acid metabolism. Increasing NAD+ levels by supplementing with the precursor nicotinamide mononucleotide (NMN) improves cardiac function in multiple mouse models of heart failure. While NAD+ 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 is via activation of the mitochondrial NAD+-dependent protein deacetylase sirtuin 3 (SIRT3). Therefore, we set-out to assess the therapeutic efficacy of NMN and the role of SIRT3 in a genetic mouse model of cardiomyopathy in Friedreich’s Ataxia (FXNKO). At baseline, the FXNKO heart has mitochondrial protein hyperacetylation, reduced SIRT3 mRNA expression, and increased demand for NAD+. Remarkably, NMN administered to FXNKO mice restored cardiac function to levels near normal. To determine whether SIRT3 is required for NMN therapeutic efficacy, we generated SIRT3KO and SIRT3KO/FXNKO (dKO) knockout models. The improvement in cardiac function upon NMN treatment in the FXNKO is lost in the dKO model, demonstrating that the effects of NMN are dependent upon cardiac SIRT3. These results demonstrate that NAD+ therapy leads to improvements in both cardiac and extra-cardiac metabolic function and energy metabolism. Furthermore, we find a key role for SIRT3 in mediating these cardioprotective effects. Taken together, these results serve as important preclinical data for NMN supplementation or SIRT3 activator therapy in patients with inborn errors in fatty acid metabolism and cardiomyopathy.
Financial Support: We thank the Freidriech’s Ataxia Research Alliance (FARA)