Generation, Release, and Uptake of the NAD Precursor Nicotinic Acid Riboside by Human Cells

Kulikova, Veronika; Shabalin, Konstantin A.; Nerinovski, Kirill; Dölle, Christian; Niere, Marc; Yakimov, Alexander; Redpath, Philip; Khodorkovskiy, Mikhail; Migaud, Marie E.; Ziegler, Mathias; Aa, Nikiforov

doi:10.1074/jbc.m115.664458

Cited by 76 publications

(64 citation statements)

References 30 publications

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“…Accordingly, labeled NR was readily detectable in liver, but not in skeletal muscle (Figure 6E, F). Unlabeled NR was also detectable in both tissues and notably suppressed in mutant muscles, suggesting the existence of a naturally occurring pool capable of interconverting with NMN, perhaps mediated by 5’-nucleotidases (Grozio et al, 2013; Kulikova et al, 2015). The minute amount of dual-labeled NAD observed in muscle indicates that direct utilization of NR by the muscle does occur.…”

Section: Resultsmentioning

confidence: 99%

Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle

et al. 2016

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Summary NAD is an obligate co-factor for the catabolism of metabolic fuels in all cell types. However, the availability of NAD in several tissues can become limited during genotoxic stress and the course of natural aging. The point at which NAD restriction imposes functional limitations on tissue physiology remains unknown. We examined this question in murine skeletal muscle by specifically deleting Nampt, an essential enzyme in the NAD salvage pathway. Knockout mice exhibited a dramatic 85% decline in intramuscular NAD content, accompanied by fiber degeneration and progressive loss of both muscle strength and treadmill endurance. Administration of the NAD precursor nicotinamide riboside rapidly ameliorated functional deficits and restored muscle mass, despite having only a modest effect on the intramuscular NAD pool. Additionally, lifelong overexpression of Nampt preserved muscle NAD levels and exercise capacity in aged mice, supporting a critical role for tissue-autonomous NAD homeostasis in maintaining muscle mass and function.

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Section: Resultsmentioning

confidence: 99%

Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle

et al. 2016

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“…NAR, like NR, is metabolized by NRKs to NAMN and then to NAAD by NMNATs [40]. However, NAAD requires final amidation to NAD + via NAD synthetase [41].…”

Section: Resultsmentioning

confidence: 99%

Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells

Fletcher

Ratajczak

Doig

et al. 2017

Molecular Metabolism

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ObjectiveAugmenting nicotinamide adenine dinucleotide (NAD+) availability may protect skeletal muscle from age-related metabolic decline. Dietary supplementation of NAD+ precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) appear efficacious in elevating muscle NAD+. Here we sought to identify the pathways skeletal muscle cells utilize to synthesize NAD+ from NMN and NR and provide insight into mechanisms of muscle metabolic homeostasis.MethodsWe exploited expression profiling of muscle NAD+ biosynthetic pathways, single and double nicotinamide riboside kinase 1/2 (NRK1/2) loss-of-function mice, and pharmacological inhibition of muscle NAD+ recycling to evaluate NMN and NR utilization.ResultsSkeletal muscle cells primarily rely on nicotinamide phosphoribosyltransferase (NAMPT), NRK1, and NRK2 for salvage biosynthesis of NAD+. NAMPT inhibition depletes muscle NAD+ availability and can be rescued by NR and NMN as the preferred precursors for elevating muscle cell NAD+ in a pathway that depends on NRK1 and NRK2. Nrk2 knockout mice develop normally and show subtle alterations to their NAD+ metabolome and expression of related genes. NRK1, NRK2, and double KO myotubes revealed redundancy in the NRK dependent metabolism of NR to NAD+. Significantly, these models revealed that NMN supplementation is also dependent upon NRK activity to enhance NAD+ availability.ConclusionsThese results identify skeletal muscle cells as requiring NAMPT to maintain NAD+ availability and reveal that NRK1 and 2 display overlapping function in salvage of exogenous NR and NMN to augment intracellular NAD+ availability.

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“…Human concentrative nucleoside transporter 3 was most efficacious as a nucleoside transporter of both BR and TZ in transfected xenopus oocytes [112]. Recent data suggests that both NR and NaR could be produced in mammalian cells and released extracellularly, and could thereby be produced in mammals as NAD + precursors [113], suggesting possible intercellular metabolic networks involving NR and NaR creation, release and transport into other cells. In addition, an NR degrading and possibly NaR degradative pathway may also help explain some of the effects of NR and NaR on cells and tissues, as first described by Kornberg [114].…”

Section: Pathways and Enzymes To Make Nad+ From Nucleosidesmentioning

confidence: 99%

NAD + metabolism: Bioenergetics, signaling and manipulation for therapy

Yang

Sauve

2016

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

382

307

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We survey the historical development of scientific knowledge surrounding Vitamin B3, and describe the active metabolite forms of Vitamin B3, the pyridine dinucleotides NAD+ and NADP+ which are essential to cellular processes of energy metabolism, cell protection and biosynthesis. The study of NAD+ has become reinvigorated by new understandings that dynamics within NAD+ metabolism trigger major signaling processes coupled to effectors (sirtuins, PARPs, and CD38) that reprogram cellular metabolism using NAD+ as an effector substrate. Cellular adaptations include stimulation of mitochondrial biogenesis, a process fundamental to adjusting cellular and tissue physiology to reduced nutrient availability and/or increased energy demand. Several metabolic pathways converge to NAD+, including tryptophan-derived de novo pathways, nicotinamide salvage pathways, nicotinic acid salvage and nucleoside salvage pathways incorporating nicotinamide riboside and nicotinic acid riboside. Key discoveries highlight a therapeutic potential for targeting NAD+ biosynthetic pathways for treatment of human diseases. A recent emergence of understanding that NAD+ homeostasis is vulnerable to aging and disease processes has stimulated testing to determine if replenishment or augmentation of cellular or tissue NAD+ can have ameliorative effects on aging or disease phenotypes. This experimental approach has provided several proof of concept successes demonstrating that replenishment or augmentation of NAD+ concentrations can provide ameliorative or curative benefits. Thus NAD+ metabolic pathways can provide key biomarkers and parameters for assessing and modulating organism health.

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Generation, Release, and Uptake of the NAD Precursor Nicotinic Acid Riboside by Human Cells

Cited by 76 publications

References 30 publications

Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle

Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle

Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells

NAD + metabolism: Bioenergetics, signaling and manipulation for therapy

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