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Publication
Increasing NAD synthesis in muscle via nicotinamide phosphoribosyltransferase is
not sufficient to promote oxidative metabolism.
Authors Frederick DW, Davis JG, Dávila A, Agarwal B, Michan S, Puchowicz MA,
Nakamaru-Ogiso E, Baur JA
Submitted By Submitted Externally on 7/24/2015
Status Published
Journal The Journal of biological chemistry
Year 2015
Date Published 1/16/2015
Volume : Pages 290 : 1546 - 1558
PubMed Reference 25411251
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 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.




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