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

Mol Metab. 2017 May 29;6(8):819-832. doi: 10.1016/j.molmet.2017.05.011. eCollection 2017 Aug.

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.

Keywords: Energy metabolism; NAD+; Nicotinamide riboside; Skeletal muscle.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cells, Cultured
  • Cytokines / metabolism
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle Fibers, Skeletal / metabolism*
  • Niacinamide / analogs & derivatives*
  • Niacinamide / metabolism
  • Nicotinamide Mononucleotide / metabolism*
  • Nicotinamide Phosphoribosyltransferase / metabolism
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*

Substances

  • Cytokines
  • nicotinamide-beta-riboside
  • Nicotinamide Mononucleotide
  • Niacinamide
  • Nicotinamide Phosphoribosyltransferase
  • nicotinamide phosphoribosyltransferase, mouse
  • Phosphotransferases (Alcohol Group Acceptor)
  • Nmrk1 protein, mouse
  • Nmrk2 protein, mouse