Dataset Information

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

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.

SUBMITTER: Fletcher RS

PROVIDER: S-EPMC5518663 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Publications

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

Fletcher Rachel S RS Ratajczak Joanna J Doig Craig L CL Oakey Lucy A LA Callingham Rebecca R Da Silva Xavier Gabriella G Garten Antje A Elhassan Yasir S YS Redpath Philip P Migaud Marie E ME Philp Andrew A Brenner Charles C Canto Carles C Lavery Gareth G GG

Molecular metabolism 20170529 8

<h4>Objective</h4>Augmenting nicotinamide adenine dinucleotide (NAD<sup>+</sup>) availability may protect skeletal muscle from age-related metabolic decline. Dietary supplementation of NAD<sup>+</sup> precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) appear efficacious in elevating muscle NAD<sup>+</sup>. Here we sought to identify the pathways skeletal muscle cells utilize to synthesize NAD<sup>+</sup> from NMN and NR and provide insight into mechanisms of muscle metab ...[more]

PMID: 28752046

Similar Datasets

Project description:BACKGROUND:Nicotinamide riboside (NR) is an NAD+ precursor that boosts cellular NAD+ concentrations. Preclinical studies have shown profound metabolic health effects after NR supplementation. OBJECTIVES:We aimed to investigate the effects of 6 wk NR supplementation on insulin sensitivity, mitochondrial function, and other metabolic health parameters in overweight and obese volunteers. METHODS:A randomized, double-blinded, placebo-controlled, crossover intervention study was conducted in 13 healthy overweight or obese men and women. Participants received 6 wk NR (1000 mg/d) and placebo supplementation, followed by broad metabolic phenotyping, including hyperinsulinemic-euglycemic clamps, magnetic resonance spectroscopy, muscle biopsies, and assessment of ex vivo mitochondrial function and in vivo energy metabolism. RESULTS:Markers of increased NAD+ synthesis-nicotinic acid adenine dinucleotide and methyl nicotinamide-were elevated in skeletal muscle after NR compared with placebo. NR increased body fat-free mass (62.65% ± 2.49% compared with 61.32% ± 2.58% in NR and placebo, respectively; change: 1.34% ± 0.50%, P = 0.02) and increased sleeping metabolic rate. Interestingly, acetylcarnitine concentrations in skeletal muscle were increased upon NR (4558 ± 749 compared with 3025 ± 316 pmol/mg dry weight in NR and placebo, respectively; change: 1533 ± 683 pmol/mg dry weight, P = 0.04) and the capacity to form acetylcarnitine upon exercise was higher in NR than in placebo (2.99 ± 0.30 compared with 2.40 ± 0.33 mmol/kg wet weight; change: 0.53 ± 0.21 mmol/kg wet weight, P = 0.01). However, no effects of NR were found on insulin sensitivity, mitochondrial function, hepatic and intramyocellular lipid accumulation, cardiac energy status, cardiac ejection fraction, ambulatory blood pressure, plasma markers of inflammation, or energy metabolism. CONCLUSIONS:NR supplementation of 1000 mg/d for 6 wk in healthy overweight or obese men and women increased skeletal muscle NAD+ metabolites, affected skeletal muscle acetylcarnitine metabolism, and induced minor changes in body composition and sleeping metabolic rate. However, no other metabolic health effects were observed.This trial was registered at clinicaltrials.gov as NCT02835664.

Dataset Information

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

Objective

Methods

Results

Conclusions

Publications

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

Similar Datasets

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