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

Rachel S Fletcher; Joanna Ratajczak; Craig L Doig; Lucy A Oakey; Rebecca Callingham; Gabriella Da Silva Xavier; Antje Garten; Yasir S Elhassan; Philip Redpath; Marie E Migaud; Andrew Philp; Charles Brenner; Carles Canto; Gareth G Lavery

doi:10.1016/j.molmet.2017.05.011

Back

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

Journal article

Open access

Peer reviewed

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

Rachel S Fletcher, Joanna Ratajczak, Craig L Doig, Lucy A Oakey, Rebecca Callingham, Gabriella Da Silva Xavier, Antje Garten, Yasir S Elhassan, Philip Redpath, Marie E Migaud, …

Molecular Metabolism, Vol.6(8), pp.819-832

08/2017

DOI: 10.1016/j.molmet.2017.05.011

PMCID: PMC5518663

PMID: 28752046

Files and links (1)

url

https://doi.org/10.1016/j.molmet.2017.05.011View

Published (Version of record) Open Access

Abstract

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. 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. 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. 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. •NRK1 and NRK2 are expressed in skeletal muscle and display redundancy in converting NR and NMN to NAD+.•NRK1 and NRK2 are dispensable for maintaining basal skeletal muscle cell NAD+.•Exogenous NMN salvage to NAD+ is NRK dependent.

Energy Metabolism

NAD

Nicotinamide riboside

Skeletal muscle

Details

Title: Subtitle: Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells
Creators: Rachel S Fletcher - Institute of Metabolism and Systems Research, 2nd Floor IBR Tower, University of Birmingham, Birmingham, B15 2TT, UK
Joanna Ratajczak - Nestlé Institute of Health Sciences (NIHS), Lausanne, CH-1015, Switzerland
Craig L Doig - Institute of Metabolism and Systems Research, 2nd Floor IBR Tower, University of Birmingham, Birmingham, B15 2TT, UK
Lucy A Oakey - Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TH, UK
Rebecca Callingham - Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, W12 0NN, UK
Gabriella Da Silva Xavier - Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, W12 0NN, UK
Antje Garten - Institute of Metabolism and Systems Research, 2nd Floor IBR Tower, University of Birmingham, Birmingham, B15 2TT, UK
Yasir S Elhassan - Institute of Metabolism and Systems Research, 2nd Floor IBR Tower, University of Birmingham, Birmingham, B15 2TT, UK
Philip Redpath - Mitchell Cancer Institute, 1660 Springhill Avenue, Mobile, AL, 36604, USA
Marie E Migaud - Mitchell Cancer Institute, 1660 Springhill Avenue, Mobile, AL, 36604, USA
Andrew Philp - School of Sport Exercise and Rehabilitation Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
Charles Brenner - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA
Carles Canto - Nestlé Institute of Health Sciences (NIHS), Lausanne, CH-1015, Switzerland
Gareth G Lavery - Institute of Metabolism and Systems Research, 2nd Floor IBR Tower, University of Birmingham, Birmingham, B15 2TT, UK
Resource Type: Journal article
Publication Details: Molecular Metabolism, Vol.6(8), pp.819-832
DOI: 10.1016/j.molmet.2017.05.011
PMID: 28752046
PMCID: PMC5518663
NLM abbreviation: Mol Metab
ISSN: 2212-8778
eISSN: 2212-8778
Publisher: Elsevier GmbH
Grant note: name: Wellcome Trust Senior Fellowship, award: GGL-104612/Z/14/Z; name: Marie Sklodowska-Curie, award: AG-No 705869; name: Nestlé Institute of Health Sciences; name: Roy J. Carver Trust; DOI: 10.13039/100000002, name: National Institutes of Health, award: CB-R21-AA022371; name: Medical Research Council; name: University of Birmingham Dynamic Investment Fund
Language: English
Date published: 08/2017
Academic Unit: Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9983788597102771

Metrics

22 Record Views

102 Times Cited - Web of Science