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Open Access 25-03-2024 | Insulins | Original Contribution

Insulin and glycolysis dependency of cardioprotection by nicotinamide riboside

Authors: Y. Xiao, Q. Wang, H. Zhang, R. Nederlof, D. Bakker, B. A. Siadari, M. W. Wesselink, B. Preckel, N. C. Weber, M. W. Hollmann, B. V. Schomakers, M. van Weeghel, C. J. Zuurbier

Published in: Basic Research in Cardiology | Issue 3/2024

Abstract

Decreased nicotinamide adenine dinucleotide (NAD⁺) levels contribute to various pathologies such as ageing, diabetes, heart failure and ischemia–reperfusion injury (IRI). Nicotinamide riboside (NR) has emerged as a promising therapeutic NAD⁺ precursor due to efficient NAD⁺ elevation and was recently shown to be the only agent able to reduce cardiac IRI in models employing clinically relevant anesthesia. However, through which metabolic pathway(s) NR mediates IRI protection remains unknown. Furthermore, the influence of insulin, a known modulator of cardioprotective efficacy, on the protective effects of NR has not been investigated. Here, we used the isolated mouse heart allowing cardiac metabolic control to investigate: (1) whether NR can protect the isolated heart against IRI, (2) the metabolic pathways underlying NR-mediated protection, and (3) whether insulin abrogates NR protection. NR protection against cardiac IRI and effects on metabolic pathways employing metabolomics for determination of changes in metabolic intermediates, and ¹³C-glucose fluxomics for determination of metabolic pathway activities (glycolysis, pentose phosphate pathway (PPP) and mitochondrial/tricarboxylic acid cycle (TCA cycle) activities), were examined in isolated C57BL/6N mouse hearts perfused with either (a) glucose + fatty acids (FA) (“mild glycolysis group”), (b) lactate + pyruvate + FA (“no glycolysis group”), or (c) glucose + FA + insulin (“high glycolysis group”). NR increased cardiac NAD⁺ in all three metabolic groups. In glucose + FA perfused hearts, NR reduced IR injury, increased glycolytic intermediate phosphoenolpyruvate (PEP), TCA intermediate succinate and PPP intermediates ribose-5P (R5P) / sedoheptulose-7P (S7P), and was associated with activated glycolysis, without changes in TCA cycle or PPP activities. In the “no glycolysis” hearts, NR protection was lost, whereas NR still increased S7P. In the insulin hearts, glycolysis was largely accelerated, and NR protection abrogated. NR still increased PPP intermediates, with now high ¹³C-labeling of S7P, but NR was unable to increase metabolic pathway activities, including glycolysis. Protection by NR against IRI is only present in hearts with low glycolysis, and is associated with activation of glycolysis. When activation of glycolysis was prevented, through either examining “no glycolysis” hearts or “high glycolysis” hearts, NR protection was abolished. The data suggest that NR’s acute cardioprotective effects are mediated through glycolysis activation and are lost in the presence of insulin because of already elevated glycolysis.

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Title: Insulin and glycolysis dependency of cardioprotection by nicotinamide riboside
Authors: Y. Xiao
Q. Wang
H. Zhang
R. Nederlof
D. Bakker
B. A. Siadari
M. W. Wesselink
B. Preckel
N. C. Weber
M. W. Hollmann
B. V. Schomakers
M. van Weeghel
C. J. Zuurbier
Publication date: 25-03-2024
Publisher: Springer Berlin Heidelberg
Keywords: Insulins
Insulins
Published in: Basic Research in Cardiology / Issue 3/2024
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-024-01042-4

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Insulin and glycolysis dependency of cardioprotection by nicotinamide riboside

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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