Are you an EPFL student looking for a semester project?
Work with us on data science and visualisation projects, and deploy your project as an app on top of Graph Search.
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.
Johan Auwerx, Xiaoxu Li, Mario Romani, Tanes Imamura de Lima, Sandra Rodriguez Lopez, Jean-David Horacio Morel, Hao Li, Martin Rainer Wohlwend, Pirkka-Pekka Untamo Laurila, Ludger Jan Elzuë Goeminne, Barbara Moreira Crisol, Changmyung Oh, Dohyun Park
Johan Auwerx, Olivier Burri, Xiaoxu Li, Tanes Imamura de Lima, Giacomo Vincenzo Giorgio Von Alvensleben, Martin Rainer Wohlwend, Pirkka-Pekka Untamo Laurila, Ludger Jan Elzuë Goeminne, Barbara Moreira Crisol, Amélia Lalou, Renata Mangione