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


ABSTRACT:

Objective

Augmenting 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.

Methods

We 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.

Results

Skeletal 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.

Conclusions

These 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.

SUBMITTER: Fletcher RS 

PROVIDER: S-EPMC5518663 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

Fletcher Rachel S RS   Ratajczak Joanna J   Doig Craig L CL   Oakey Lucy A LA   Callingham Rebecca R   Da Silva Xavier Gabriella G   Garten Antje A   Elhassan Yasir S YS   Redpath Philip P   Migaud Marie E ME   Philp Andrew A   Brenner Charles C   Canto Carles C   Lavery Gareth G GG  

Molecular metabolism 20170529 8


<h4>Objective</h4>Augmenting nicotinamide adenine dinucleotide (NAD<sup>+</sup>) availability may protect skeletal muscle from age-related metabolic decline. Dietary supplementation of NAD<sup>+</sup> precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) appear efficacious in elevating muscle NAD<sup>+</sup>. Here we sought to identify the pathways skeletal muscle cells utilize to synthesize NAD<sup>+</sup> from NMN and NR and provide insight into mechanisms of muscle metab  ...[more]

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