Nicotinamide Riboside Kinases Display Redundancy in Mediating Nicotinamide Mononucleotide and Nicotinamide Riboside Metabolism in Skeletal Muscle Cells

Overview

Journal Mol Metab

Specialty Cell Biology

Date 2017 Jul 29

PMID 28752046

Citations 67

Authors

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

Affiliations

Soon will be listed here.

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.

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