Abstract
ObjectiveAugmenting 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. MethodsWe 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. ResultsSkeletal 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. ConclusionsThese 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.
Highlights
Nicotinamide adenine dinucleotide (NADþ) was first described as a vital cofactor in cellular redox reactions important to cellular energy metabolism [1,2]
To better understand the roles the NRKs play in the context of the rate limiting enzymes nicotinamide phosphoribosyltransferase (NAMPT) and NADsyn1, we examined their expression in a range of tissues to determine tissue specificity
Following fractionation of skeletal muscle tissue enriched into microsomes, cytosol, and mitochondria we show that NRK2, NRK1, and NAMPT are predominantly localized to cytosol (Figure 1L)
Summary
Nicotinamide adenine dinucleotide (NADþ) was first described as a vital cofactor in cellular redox reactions important to cellular energy metabolism [1,2]. NADþ serves as a consumed substrate for enzymes such as sirtuins that post translationally modify proteins by deacetylation, yielding nicotinamide (NAM) and 20-and 3-O-aceyl-ADP ribose in the process [3]. Because of the activity of NADþ consuming enzymes, replenishment of NADþ through biosynthesis and salvage pathways is vital [7,8]. NADþ can be synthesized de novo from tryptophan and by salvage of nicotinic acid (NA), a form of vitamin B3, via the Preiss-Handler pathway [9,10]. A final route to NADþ is the salvage and phosphorylation of the recently discovered form of vitamin B3 nicotinamide riboside (NR) to NMN, through the nicotinamide riboside
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