Endocrine Abstracts

Exercise has undisputed health benefits mediated through metabolic adaptation in skeletal muscle. In contrast, a sedentary lifestyle, leads to impaired metabolic function and negative health outcomes such as insulin resistance and sarcopenia. Whilst exercise improves skeletal muscle metabolism, how the process is co-ordinated at a cellular level remains unclear. Recently, NAD⁺ has been suggested to play an important role in muscle adaptation, acting as a substrate for NAD⁺-sensing sirtuin (SIRT) family of deacetylases linking NAD⁺ signalling to adaptation. A newly identified source of NAD⁺ is salvage of the dietary vitamin nicotinamide riboside (NR) through the nicotinamide riboside kinase 2 (NMRK2) pathway. However, there is little known about the contribution of NMRK2 to NAD⁺ salvage and maintenance of NAD⁺ in skeletal muscle.

Recent studies investigating muscle in hexose-6-phosphate dehydrogenase (H6PDH) KO mice identified NMRK2 as a regulated stress response gene, being up-regulated (>50-fold in fast twitch muscle and greater than tenfold in slow twitch muscle), and associated with increased NAD⁺ levels. NMRK2 expression increases during muscle differentiation and shows a dose-dependent increases in expression following overnight glucose restriction (shifting from 25 to 4 mM), again associated with increased NAD⁺ levels. Conversely, myotubes transfected with NMRK2 siRNA had a significant reduction in cellular NAD⁺(~30%). Knockdown of NMRK2 also had significant effects on the expression of mitochondrial NAD⁺ dependent and NAD⁺ associated enzymes methylenetetrahydrofolate dehydrogenase (folate biosynthesis), citrate synthase (TCA cycle) and mitochondrial cytochrome oxidaseC1 (fatty acid oxidation). Using microarrays we can show that NMRK2 is the most abundantly expressed gene amongst the few genes in muscle that regulate NAD⁺ biosynthesis. Based on these ongoing studies, which are now focusing on sirtuin activity, we hypothesise that NMRK2 is a fundamental regulator of NAD⁺ biosynthesis and is crucial to the ability of muscle to regulate metabolic adaptation and homeostasis.