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Title: Vitamin B3 salvage and NAD⁺ metabolism in skeletal muscle
Author: Fletcher, Rachel
ISNI:       0000 0004 6423 7621
Awarding Body: University of Birmingham
Current Institution: University of Birmingham
Date of Award: 2017
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Nicotinamide adenine dinucleotide (NAD⁺)) is both an essential redox coenzyme and a substrate for NAD⁺ consuming enzymes, such as the sirtuins, which adapt transcriptional programmes to increase energy availability. Skeletal muscle is a major regulator of energy metabolism and its function is impaired with ageing. Uncovering the key routes regulating NAD⁺ availability may provide valuable insight into novel aspects of skeletal muscle metabolic health. Data presented here identifies a limited set of enzymes important for skeletal muscle NAD⁺ -biosynthesis namely; nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide riboside kinases (NMRK) 1 and 2, which salvage vitamin B3s nicotinamide (NAM) and nicotinamide riboside (NR) to NAD⁺. NAMPT was confirmed vital for recycling of NAM, with NAD+ depleted in myotubes following NAMPT inhibition. Single and double NMRK knockout mouse models found NMRK activity nonessential for maintaining basal NAD⁺, with activity restricted by NR availability. Exogenous NR delivery enhanced NAD⁺ and recovered the effects of NAD⁺ depletion following NAMPT inhibition. NMRK2 was determined highly muscle-specific; although energy signalling was mostly unperturbed in NMRK2KOs, in vivo data indicated impaired metabolic flexibility following high fat diet. While the muscle-specific role of NMRK2 requires further investigation, this thesis identifies NMRK1/2 as important therapeutic targets for enhancing NAD⁺ by NR supplementation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QH301 Biology