Vitamin B3 salvage and NAD\(^+\) metabolism in skeletal muscle

Fletcher, Rachel (2017). Vitamin B3 salvage and NAD\(^+\) metabolism in skeletal muscle. University of Birmingham. Ph.D.

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Abstract

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.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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