title: Increasing NAD synthesis in muscle via nicotinamide phosphoribosyltransferase is not sufficient to promote oxidative metabolism.
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.
authors.affiliation: From the Department of Physiology, Institute for Diabetes, Obesity, and Metabolism and.
authors.forename: David W
authors.initials: DW
authors.lastname: Frederick
authors.affiliation: From the Department of Physiology, Institute for Diabetes, Obesity, and Metabolism and.
authors.forename: James G
authors.initials: JG
authors.lastname: Davis
authors.affiliation: From the Department of Physiology, Institute for Diabetes, Obesity, and Metabolism and.
authors.forename: Antonio
authors.initials: A
authors.lastname: Dávila
authors.affiliation: From the Department of Physiology, Institute for Diabetes, Obesity, and Metabolism and.
authors.forename: Beamon
authors.initials: B
authors.lastname: Agarwal
authors.affiliation: Instituto Nacional de Geriatría, México, Distrito Federal 10200, México, and.
authors.forename: Shaday
authors.initials: S
authors.lastname: Michan
authors.affiliation: Department of Nutrition, Mouse Metabolic Phenotyping Center, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Puchowicz
authors.affiliation: Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Eiko
authors.initials: E
authors.lastname: Nakamaru-Ogiso
authors.affiliation: From the Department of Physiology, Institute for Diabetes, Obesity, and Metabolism and baur@mail.med.upenn.edu.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Baur
mesh_terms: D000818:Animals; D001665:Binding Sites; D002151:Calorimetry; D002851:Chromatography, High Pressure Liquid; D016207:Cytokines / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008931:Mitochondria, Muscle / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009243:NAD / Q000096:biosynthesis* / Q000378:metabolism; D009537:Nicotinamide Mononucleotide / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
chemical_list: D016207:Cytokines; D009243:NAD; D009537:Nicotinamide Mononucleotide; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse; D011065:Poly(ADP-ribose) Polymerases; D010100:Oxygen
keywords: Mitochondrial Metabolism; NAD Biosynthesis; NAMPT; NMN; Nicotinamide; Nicotinamide Adenine Dinucleotide (NAD); Nicotinamide Adenine Dinucleotide (NADH); Nicotinamide Riboside; Redox Regulation; Skeletal Muscle Metabolism