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

Rachel S Fletcher, Joanna Ratajczak, Craig L Doig, Lucy A Oakey, Rebecca Callingham, Gabriella Da Silva Xavier, Antje Garten, Yasir S Elhassan, Philip Redpath, Marie E Migaud, Andrew Philp, Charles Brenner, Carles Canto, Gareth G Lavery

Research output: Contribution to journalArticlepeer-review

49 Citations (Scopus)
218 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)819-832
Number of pages14
JournalMolecular metabolism
Volume6
Issue number8
Early online date29 May 2017
DOIs
Publication statusPublished - Aug 2017

Keywords

  • Skeletal muscle
  • NAD+
  • Energy metabolism
  • Nicotinamide riboside

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