Nicotinamide riboside preserves cardiac function in a mouse model of dilated cardiomyopathy

Nicolas Diguet; Samuel A.J. Trammell; Cynthia Tannous; Robin Deloux; Jérôme Piquereau; Nathalie Mougenot; Anne Gouge; Mélanie Gressette; Boris Manoury; Jocelyne Blanc; Marie Breton; Jean François Decaux; Gareth G. Lavery; István Baczkó; Joffrey Zoll; Anne Garnier; Zhenlin Li; Charles Brenner; Mathias Mericskay

doi:10.1161/circulationaha.116.026099

Nicotinamide riboside preserves cardiac function in a mouse model of dilated cardiomyopathy

Nicolas Diguet, Samuel A.J. Trammell, Cynthia Tannous, Robin Deloux, Jérôme Piquereau, Nathalie Mougenot, Anne Gouge, Mélanie Gressette, Boris Manoury, Jocelyne Blanc, Marie Breton, Jean François Decaux, Gareth G. Lavery, István Baczkó, Joffrey Zoll, Anne Garnier, Zhenlin Li, Charles Brenner, Mathias Mericskay^*

^*Corresponding author af dette arbejde

85 Citationer (Scopus)

Abstract

BACKGROUND: Myocardial metabolic impairment is a major feature in chronic heart failure. As the major coenzyme in fuel oxidation and oxidative phosphorylation and a substrate for enzymes signaling energy stress and oxidative stress response, nicotinamide adenine dinucleotide (NAD ⁺ ) is emerging as a metabolic target in a number of diseases including heart failure. Little is known on the mechanisms regulating homeostasis of NAD ⁺ in the failing heart. METHODS: To explore possible alterations of NAD ⁺ homeostasis in the failing heart, we quantified the expression of NAD ⁺ biosynthetic enzymes in the human failing heart and in the heart of a mouse model of dilated cardiomyopathy (DCM) triggered by Serum Response Factor transcription factor depletion in the heart (SRF ^HKO ) or of cardiac hypertrophy triggered by transverse aorta constriction. We studied the impact of NAD ⁺ precursor supplementation on cardiac function in both mouse models. RESULTS: We observed a 30% loss in levels of NAD ⁺ in the murine failing heart of both DCM and transverse aorta constriction mice that was accompanied by a decrease in expression of the nicotinamide phosphoribosyltransferase enzyme that recycles the nicotinamide precursor, whereas the nicotinamide riboside kinase 2 (NMRK2) that phosphorylates the nicotinamide riboside precursor is increased, to a higher level in the DCM (40-fold) than in transverse aorta constriction (4-fold). This shift was also observed in human failing heart biopsies in comparison with nonfailing controls. We show that the Nmrk2 gene is an AMP-activated protein kinase and peroxisome proliferator-activated receptor α responsive gene that is activated by energy stress and NAD ⁺ depletion in isolated rat cardiomyocytes. Nicotinamide riboside efficiently rescues NAD ⁺ synthesis in response to FK866-mediated inhibition of nicotinamide phosphoribosyltransferase and stimulates glycolysis in cardiomyocytes. Accordingly, we show that nicotinamide riboside supplementation in food attenuates the development of heart failure in mice, more robustly in DCM, and partially after transverse aorta constriction, by stabilizing myocardial NAD ⁺ levels in the failing heart. Nicotinamide riboside treatment also robustly increases the myocardial levels of 3 metabolites, nicotinic acid adenine dinucleotide, methylnicotinamide, and N1-methyl-4-pyridone-5-carboxamide, that can be used as validation biomarkers for the treatment. CONCLUSIONS: The data show that nicotinamide riboside, the most energy-efficient among NAD precursors, could be useful for treatment of heart failure, notably in the context of DCM, a disease with few therapeutic options.

Originalsprog	Engelsk
Bogserie	Circulation
Vol/bind	137
Udgave nummer	21
Sider (fra-til)	2256-2273
Antal sider	18
ISSN	0009-7322
DOI	https://doi.org/10.1161/circulationaha.116.026099
Status	Udgivet - 2018
Udgivet eksternt	Ja

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10.1161/circulationaha.116.026099

CIRCULATIONAHA.116.026099Forlagets udgivne version, 2,08 MB

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Diguet, N., Trammell, S. A. J., Tannous, C., Deloux, R., Piquereau, J., Mougenot, N., Gouge, A., Gressette, M., Manoury, B., Blanc, J., Breton, M., Decaux, J. F., Lavery, G. G., Baczkó, I., Zoll, J., Garnier, A., Li, Z., Brenner, C., & Mericskay, M. (2018). Nicotinamide riboside preserves cardiac function in a mouse model of dilated cardiomyopathy. Circulation, 137(21), 2256-2273. https://doi.org/10.1161/circulationaha.116.026099

Diguet, N, Trammell, SAJ, Tannous, C, Deloux, R, Piquereau, J, Mougenot, N, Gouge, A, Gressette, M, Manoury, B, Blanc, J, Breton, M, Decaux, JF, Lavery, GG, Baczkó, I, Zoll, J, Garnier, A, Li, Z, Brenner, C & Mericskay, M 2018, 'Nicotinamide riboside preserves cardiac function in a mouse model of dilated cardiomyopathy', Circulation, bind 137, nr. 21, s. 2256-2273. https://doi.org/10.1161/circulationaha.116.026099

@article{77a09de314914a328bc789ba234dd3cb,

title = "Nicotinamide riboside preserves cardiac function in a mouse model of dilated cardiomyopathy",

abstract = " BACKGROUND: Myocardial metabolic impairment is a major feature in chronic heart failure. As the major coenzyme in fuel oxidation and oxidative phosphorylation and a substrate for enzymes signaling energy stress and oxidative stress response, nicotinamide adenine dinucleotide (NAD + ) is emerging as a metabolic target in a number of diseases including heart failure. Little is known on the mechanisms regulating homeostasis of NAD + in the failing heart. METHODS: To explore possible alterations of NAD + homeostasis in the failing heart, we quantified the expression of NAD + biosynthetic enzymes in the human failing heart and in the heart of a mouse model of dilated cardiomyopathy (DCM) triggered by Serum Response Factor transcription factor depletion in the heart (SRF HKO ) or of cardiac hypertrophy triggered by transverse aorta constriction. We studied the impact of NAD + precursor supplementation on cardiac function in both mouse models. RESULTS: We observed a 30% loss in levels of NAD + in the murine failing heart of both DCM and transverse aorta constriction mice that was accompanied by a decrease in expression of the nicotinamide phosphoribosyltransferase enzyme that recycles the nicotinamide precursor, whereas the nicotinamide riboside kinase 2 (NMRK2) that phosphorylates the nicotinamide riboside precursor is increased, to a higher level in the DCM (40-fold) than in transverse aorta constriction (4-fold). This shift was also observed in human failing heart biopsies in comparison with nonfailing controls. We show that the Nmrk2 gene is an AMP-activated protein kinase and peroxisome proliferator-activated receptor α responsive gene that is activated by energy stress and NAD + depletion in isolated rat cardiomyocytes. Nicotinamide riboside efficiently rescues NAD + synthesis in response to FK866-mediated inhibition of nicotinamide phosphoribosyltransferase and stimulates glycolysis in cardiomyocytes. Accordingly, we show that nicotinamide riboside supplementation in food attenuates the development of heart failure in mice, more robustly in DCM, and partially after transverse aorta constriction, by stabilizing myocardial NAD + levels in the failing heart. Nicotinamide riboside treatment also robustly increases the myocardial levels of 3 metabolites, nicotinic acid adenine dinucleotide, methylnicotinamide, and N1-methyl-4-pyridone-5-carboxamide, that can be used as validation biomarkers for the treatment. CONCLUSIONS: The data show that nicotinamide riboside, the most energy-efficient among NAD precursors, could be useful for treatment of heart failure, notably in the context of DCM, a disease with few therapeutic options. ",

keywords = "Acetyl coenzyme A, Cardiomyopathy, Dilated, Energy metabolism, Glycolysis, Heart failure, NAD, Nicotinamide-beta-riboside, Serum response factor",

author = "Nicolas Diguet and Trammell, {Samuel A.J.} and Cynthia Tannous and Robin Deloux and J{\'e}r{\^o}me Piquereau and Nathalie Mougenot and Anne Gouge and M{\'e}lanie Gressette and Boris Manoury and Jocelyne Blanc and Marie Breton and Decaux, {Jean Fran{\c c}ois} and Lavery, {Gareth G.} and Istv{\'a}n Baczk{\'o} and Joffrey Zoll and Anne Garnier and Zhenlin Li and Charles Brenner and Mathias Mericskay",

year = "2018",

doi = "10.1161/circulationaha.116.026099",

language = "English",

volume = "137",

pages = "2256--2273",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams & Wilkins",

number = "21",

}

TY - JOUR

T1 - Nicotinamide riboside preserves cardiac function in a mouse model of dilated cardiomyopathy

AU - Diguet, Nicolas

AU - Trammell, Samuel A.J.

AU - Tannous, Cynthia

AU - Deloux, Robin

AU - Piquereau, Jérôme

AU - Mougenot, Nathalie

AU - Gouge, Anne

AU - Gressette, Mélanie

AU - Manoury, Boris

AU - Blanc, Jocelyne

AU - Breton, Marie

AU - Decaux, Jean François

AU - Lavery, Gareth G.

AU - Baczkó, István

AU - Zoll, Joffrey

AU - Garnier, Anne

AU - Li, Zhenlin

AU - Brenner, Charles

AU - Mericskay, Mathias

PY - 2018

Y1 - 2018

N2 - BACKGROUND: Myocardial metabolic impairment is a major feature in chronic heart failure. As the major coenzyme in fuel oxidation and oxidative phosphorylation and a substrate for enzymes signaling energy stress and oxidative stress response, nicotinamide adenine dinucleotide (NAD + ) is emerging as a metabolic target in a number of diseases including heart failure. Little is known on the mechanisms regulating homeostasis of NAD + in the failing heart. METHODS: To explore possible alterations of NAD + homeostasis in the failing heart, we quantified the expression of NAD + biosynthetic enzymes in the human failing heart and in the heart of a mouse model of dilated cardiomyopathy (DCM) triggered by Serum Response Factor transcription factor depletion in the heart (SRF HKO ) or of cardiac hypertrophy triggered by transverse aorta constriction. We studied the impact of NAD + precursor supplementation on cardiac function in both mouse models. RESULTS: We observed a 30% loss in levels of NAD + in the murine failing heart of both DCM and transverse aorta constriction mice that was accompanied by a decrease in expression of the nicotinamide phosphoribosyltransferase enzyme that recycles the nicotinamide precursor, whereas the nicotinamide riboside kinase 2 (NMRK2) that phosphorylates the nicotinamide riboside precursor is increased, to a higher level in the DCM (40-fold) than in transverse aorta constriction (4-fold). This shift was also observed in human failing heart biopsies in comparison with nonfailing controls. We show that the Nmrk2 gene is an AMP-activated protein kinase and peroxisome proliferator-activated receptor α responsive gene that is activated by energy stress and NAD + depletion in isolated rat cardiomyocytes. Nicotinamide riboside efficiently rescues NAD + synthesis in response to FK866-mediated inhibition of nicotinamide phosphoribosyltransferase and stimulates glycolysis in cardiomyocytes. Accordingly, we show that nicotinamide riboside supplementation in food attenuates the development of heart failure in mice, more robustly in DCM, and partially after transverse aorta constriction, by stabilizing myocardial NAD + levels in the failing heart. Nicotinamide riboside treatment also robustly increases the myocardial levels of 3 metabolites, nicotinic acid adenine dinucleotide, methylnicotinamide, and N1-methyl-4-pyridone-5-carboxamide, that can be used as validation biomarkers for the treatment. CONCLUSIONS: The data show that nicotinamide riboside, the most energy-efficient among NAD precursors, could be useful for treatment of heart failure, notably in the context of DCM, a disease with few therapeutic options.

AB - BACKGROUND: Myocardial metabolic impairment is a major feature in chronic heart failure. As the major coenzyme in fuel oxidation and oxidative phosphorylation and a substrate for enzymes signaling energy stress and oxidative stress response, nicotinamide adenine dinucleotide (NAD + ) is emerging as a metabolic target in a number of diseases including heart failure. Little is known on the mechanisms regulating homeostasis of NAD + in the failing heart. METHODS: To explore possible alterations of NAD + homeostasis in the failing heart, we quantified the expression of NAD + biosynthetic enzymes in the human failing heart and in the heart of a mouse model of dilated cardiomyopathy (DCM) triggered by Serum Response Factor transcription factor depletion in the heart (SRF HKO ) or of cardiac hypertrophy triggered by transverse aorta constriction. We studied the impact of NAD + precursor supplementation on cardiac function in both mouse models. RESULTS: We observed a 30% loss in levels of NAD + in the murine failing heart of both DCM and transverse aorta constriction mice that was accompanied by a decrease in expression of the nicotinamide phosphoribosyltransferase enzyme that recycles the nicotinamide precursor, whereas the nicotinamide riboside kinase 2 (NMRK2) that phosphorylates the nicotinamide riboside precursor is increased, to a higher level in the DCM (40-fold) than in transverse aorta constriction (4-fold). This shift was also observed in human failing heart biopsies in comparison with nonfailing controls. We show that the Nmrk2 gene is an AMP-activated protein kinase and peroxisome proliferator-activated receptor α responsive gene that is activated by energy stress and NAD + depletion in isolated rat cardiomyocytes. Nicotinamide riboside efficiently rescues NAD + synthesis in response to FK866-mediated inhibition of nicotinamide phosphoribosyltransferase and stimulates glycolysis in cardiomyocytes. Accordingly, we show that nicotinamide riboside supplementation in food attenuates the development of heart failure in mice, more robustly in DCM, and partially after transverse aorta constriction, by stabilizing myocardial NAD + levels in the failing heart. Nicotinamide riboside treatment also robustly increases the myocardial levels of 3 metabolites, nicotinic acid adenine dinucleotide, methylnicotinamide, and N1-methyl-4-pyridone-5-carboxamide, that can be used as validation biomarkers for the treatment. CONCLUSIONS: The data show that nicotinamide riboside, the most energy-efficient among NAD precursors, could be useful for treatment of heart failure, notably in the context of DCM, a disease with few therapeutic options.

KW - Acetyl coenzyme A

KW - Cardiomyopathy

KW - Dilated

KW - Energy metabolism

KW - Glycolysis

KW - Heart failure

KW - NAD

KW - Nicotinamide-beta-riboside

KW - Serum response factor

U2 - 10.1161/circulationaha.116.026099

DO - 10.1161/circulationaha.116.026099

M3 - Journal article

C2 - 29217642

AN - SCOPUS:85045481163

SN - 0009-7322

VL - 137

SP - 2256

EP - 2273

JO - Circulation

JF - Circulation

IS - 21

ER -

Nicotinamide riboside preserves cardiac function in a mouse model of dilated cardiomyopathy

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