Frederick 2014 J Biol Chem

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Frederick DW, Davis JG, Dávila A Jr, Agarwal B, Michan S, Puchowicz MA, Nakamaru-Ogiso E, Baur JA (2014) Increasing NAD synthesis in muscle via nicotinamide phosphoribosyltransferase is not sufficient to promote oxidative metabolism.. J Biol Chem. 290:1546-58.

» PMID: 25411251

Frederick DW, Davis JG, Davila A, Agarwal B, Michan S, Puchowicz MA, Nakamaru-Ogiso E, Baur JA (2014) J Biol Chem

Abstract: 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 germline deletion of major NAD-consuming enzymes, suggesting that the bioavailability of NAD is limiting for maximal oxidative capacity. However, due to 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 to the effects of dietary NAD precursors, exercise regimens, or loss of poly-ADP ribose polymerases (PARPs), 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 tissuespecific increases in NAD synthesis and suggest that critical sites of action for supplemental NAD precursors reside outside of the heart and skeletal muscle.

Keywords: NAD biosynthesis, NAD, NADH, Nicotinamide, Redox regulation, Mitochondrial metabolism, Skeletal muscle metabolism, NMN, nicotinamide riboside, Nampt

Labels: MiParea: Respiration  Pathology: Obesity 

Organism: Mouse  Tissue;cell: Skeletal muscle  Preparation: Isolated mitochondria 

Coupling state: LEAK, OXPHOS  Pathway: F, N, S, ROX  HRR: Oxygraph-2k