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

Fletcher RS; Ratajczak J; Doig CL; Oakey LA; Callingham R; Da Silva Xavier G; Garten A; Elhassan YS; Redpath P; Migaud ME; Philp A; Brenner C; Canto C; Lavery GG

doi:10.1016/j.molmet.2017.05.011

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Journal article

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

Fletcher RS 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.
Ratajczak J Nestlé Institute of Health Sciences (NIHS), Lausanne, CH-1015, Switzerland; Ecole Polytechnique Fédérale de Lausanne, Switzerland.
Doig CL 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.
Oakey LA Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TH, UK.
Callingham R Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, W12 0NN, UK.
Da Silva Xavier G Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, W12 0NN, UK.
Garten A 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.
Elhassan YS 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.
Redpath P Mitchell Cancer Institute, 1660 Springhill Avenue, Mobile, AL, 36604, USA.
Migaud ME Mitchell Cancer Institute, 1660 Springhill Avenue, Mobile, AL, 36604, USA.
Philp A School of Sport Exercise and Rehabilitation Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
Brenner C Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA.
Canto C Nestlé Institute of Health Sciences (NIHS), Lausanne, CH-1015, Switzerland; Ecole Polytechnique Fédérale de Lausanne, Switzerland.
Lavery GG 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.

2017-07-29

Published in:

Molecular metabolism. - 2017

Nicotinamide Phosphoribosyltransferase

Phosphotransferases (Alcohol Group Acceptor)

English 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.

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