Increasing NAD synthesis in muscle via nicotinamide phosphoribosyltransferase is not sufficient to promote oxidative metabolism

J Biol Chem. 2015 Jan 16;290(3):1546-58. doi: 10.1074/jbc.M114.579565. Epub 2014 Nov 19.


The NAD biosynthetic precursors nicotinamide mononucleotide and nicotinamide riboside are reported to confer resistance to metabolic defects induced by high fat feeding in part by promoting oxidative metabolism in skeletal muscle. Similar effects are obtained by germ line deletion of major NAD-consuming enzymes, suggesting that the bioavailability of NAD is limiting for maximal oxidative capacity. However, because of their systemic nature, the degree to which these interventions exert cell- or tissue-autonomous effects is unclear. Here, we report a tissue-specific approach to increase NAD biosynthesis only in muscle by overexpressing nicotinamide phosphoribosyltransferase, the rate-limiting enzyme in the salvage pathway that converts nicotinamide to NAD (mNAMPT mice). These mice display a ∼50% increase in skeletal muscle NAD levels, comparable with the effects of dietary NAD precursors, exercise regimens, or loss of poly(ADP-ribose) polymerases yet surprisingly do not exhibit changes in muscle mitochondrial biogenesis or mitochondrial function and are equally susceptible to the metabolic consequences of high fat feeding. We further report that chronic elevation of muscle NAD in vivo does not perturb the NAD/NADH redox ratio. These studies reveal for the first time the metabolic effects of tissue-specific increases in NAD synthesis and suggest that critical sites of action for supplemental NAD precursors reside outside of the heart and skeletal muscle.

Keywords: Mitochondrial Metabolism; NAD Biosynthesis; NAMPT; NMN; Nicotinamide; Nicotinamide Adenine Dinucleotide (NAD); Nicotinamide Adenine Dinucleotide (NADH); Nicotinamide Riboside; Redox Regulation; Skeletal Muscle Metabolism.

Publication types

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

MeSH terms

  • Animals
  • Binding Sites
  • Calorimetry
  • Chromatography, High Pressure Liquid
  • Cytokines / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria, Muscle / metabolism
  • Muscle, Skeletal / metabolism*
  • NAD / biosynthesis*
  • NAD / metabolism
  • Nicotinamide Mononucleotide / metabolism
  • Nicotinamide Phosphoribosyltransferase / metabolism*
  • Oxidation-Reduction
  • Oxygen / metabolism*
  • Poly(ADP-ribose) Polymerases / metabolism


  • Cytokines
  • NAD
  • Nicotinamide Mononucleotide
  • Nicotinamide Phosphoribosyltransferase
  • nicotinamide phosphoribosyltransferase, mouse
  • Poly(ADP-ribose) Polymerases
  • Oxygen