| First Author | Fletcher RS | Year | 2017 |
| Journal | Mol Metab | Volume | 6 |
| Issue | 8 | Pages | 819-832 |
| PubMed ID | 28752046 | Mgi Jnum | J:321783 |
| Mgi Id | MGI:6844526 | Doi | 10.1016/j.molmet.2017.05.011 |
| Citation | Fletcher RS, et al. (2017) Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells. Mol Metab 6(8):819-832 |
| abstractText | 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. |
