Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells
Research output: Contribution to journal › Article › peer-review
Colleges, School and Institutes
- Nestlé Institute of Health Sciences (NIHS), Lausanne, CH-1015, Switzerland; Ecole Polytechnique Fédérale de Lausanne, Switzerland.
- Centre for Endocrinology; Diabetes and Metabolism; Birmingham Health Partners; Birmingham B15 2TH UK
- Imperial College London
- Mitchell Cancer Institute, 1660 Springhill Avenue, Mobile AL, 36604, USA
- Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA.
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.
|Number of pages||14|
|Early online date||29 May 2017|
|Publication status||Published - Aug 2017|
- Skeletal muscle , NAD+ , Energy metabolism , Nicotinamide riboside