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

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

Objective

Boosting 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 to be effective in elevating muscle NAD+. Here we sought to identify the pathways mouse skeletal muscle cells utilize to create NAD+ from NMN and NR, and provide insight into mechanisms of healthy metabolism in muscle cells.

Results

Skeletal muscle cells primarily rely on key conversion pathways NAMPT (nicotinamide phosphoribosyltransferase), NRK1, and NRK2 to create NAD+. Blocking NAMPT depletes muscle NAD+ availability Which can be improved by NR and NMN. The mice that were not able to use the Nrk2 pathway to create NAD developed normally and showed subtle alterations to their NAD+ metabolome and expression of related genes. Mice lacking the NRK1, NRK2, or both pathways in their muscle fibers revealed redundancy in the NRK dependent metabolism of NR to NAD+. Significantly, these models revealed that NMN supplementation is also dependent on the NRK pathways to enhance NAD+ availability.

Conclusions

These results identify skeletal muscle cells as requiring NAMPT to maintain NAD+ availability and they reveal that NRK1 and 2 display overlapping function in bringing NR and NMN from outside the cell, into the cell where it can proceed in boosting NAD+ availability.

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