Adaptations to skeletal muscle metabolism in response to altered NAD\(^+\) bioavailability

Oakey, Lucy (2020). Adaptations to skeletal muscle metabolism in response to altered NAD\(^+\) bioavailability. University of Birmingham. Ph.D.

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Skeletal muscle is central to energy homeostasis and metabolic health. Nicotinamide adenine dinucleotide (NAD\(^+\)) is a key modulator of energy metabolism and signalling. Reduced NAD\(^+\) levels have been implicated in aging and in chronic disease states, such as diabetes. Therefore, approaches to augment NAD\(^+\) have become popular.

This work aimed to use alternative models of differing NAD\(^+\) bioavailability to investigate changes to molecular metabolism. Isotopic tracers were used and metabolic tracing was conducted to provide detailed analysis of central carbon metabolism. To achieve this combined 2D-\(^1\)H,\(^1\)\(^3\)C-heteronulcear single quantum coherence (HSQC) NMR spectroscopy and GCMS methods were employed. Further studies were conducted to explore the impact of altered NAD\(^+\) metabolism in vivo using \(^1\)\(^3\)C intravenous infusion and an exercise protocol.

Skeletal muscle showed efficient clearance of excess NAD\(^+\) thought to maintain the tightly controlled NAD\(^+\)/NADH ratio. Metabolic tracing revealed elevated mitochondrial derived aspartate production in response to inhibition of nicotinamide phosphoribosyltransferase (NAMPT). An NAD\(^+\) dependant block of glyceraldehyde phosphate dehydrogenase (GAPDH) was also evidenced through metabolite levels and label incorporation. This shows skeletal muscle retaining mitochondrial oxidative metabolism, suggesting differential effects of FK866 treatment on sub-cellular pyridine pools.

Overall the work highlighted how core carbon metabolic pathways are able to adapt to differing NAD\(^+\) bioavailability in skeletal muscle.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
Licence: All rights reserved
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: Institute of Metabolism and Systems Research
Funders: Other
Other Funders: University of Birmingham
Subjects: Q Science > Q Science (General)


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