期刊
MOLECULAR METABOLISM
卷 6, 期 8, 页码 819-832出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.molmet.2017.05.011
关键词
Skeletal muscle; NAD(+); Energy metabolism; Nicotinamide riboside
资金
- MRC PhD studentship
- Wellcome Trust Senior Fellowship [GGL-104612/Z/14/Z]
- Marie Sklodowska-Curie [705869]
- Nestle Institute of Health Sciences
- Roy J. Carver Trust
- National Institutes of Health [CB- R21-AA022371]
- Medical Research Council
- University of Birmingham Dynamic Investment Fund
- Biotechnology and Biological Sciences Research Council [BB/N001842/1] Funding Source: researchfish
- Medical Research Council [MR/K001981/1, 1227950] Funding Source: researchfish
- Marie Curie Actions (MSCA) [705869] Funding Source: Marie Curie Actions (MSCA)
- BBSRC [BB/N001842/1] Funding Source: UKRI
- MRC [MR/K001981/1] Funding Source: UKRI
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. (C) 2017 The Authors. Published by Elsevier GmbH.
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