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Mol Metab. 2017 May 29;6(8):819-832. doi: 10.1016/j.molmet.2017.05.011. eCollection 2017 Aug.

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

Author information

1
Institute of Metabolism and Systems Research, 2nd Floor IBR Tower, University of Birmingham, Birmingham, B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TH, UK.
2
Nestlé Institute of Health Sciences (NIHS), Lausanne, CH-1015, Switzerland; Ecole Polytechnique Fédérale de Lausanne, Switzerland.
3
Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TH, UK.
4
Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, W12 0NN, UK.
5
Institute of Metabolism and Systems Research, 2nd Floor IBR Tower, University of Birmingham, Birmingham, B15 2TT, UK; Leipzig University, Hospital for Children and Adolescents, Center for Pediatric Research, Liebigstrasse 19-21, 04103, Leipzig, Germany.
6
Mitchell Cancer Institute, 1660 Springhill Avenue, Mobile, AL, 36604, USA.
7
School of Sport Exercise and Rehabilitation Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
8
Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA.
9
Institute of Metabolism and Systems Research, 2nd Floor IBR Tower, University of Birmingham, Birmingham, B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TH, UK. Electronic address: g.g.lavery@bham.ac.uk.

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.

KEYWORDS:

Energy metabolism; NAD+; Nicotinamide riboside; Skeletal muscle

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