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