Investigating the physiological and functional roles of the nicotinamide riboside kinase pathway in skeletal muscle

Cartwright, David Michael (2021). Investigating the physiological and functional roles of the nicotinamide riboside kinase pathway in skeletal muscle. University of Birmingham. Ph.D.

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Skeletal muscle is a major site of energy metabolism and critical to metabolic health. Bioavailability of the redox coenzyme nicotinamide adenine dinucleotide (NAD\(^+\)) is essential for metabolic function, which is also consumed by NAD\(^+\) dependent signalling enzymes driving metabolic adaptation. Ageing and a sedentary lifestyle is accompanied by metabolic dysregulation partly attributable to a decline in skeletal muscle NAD\(^+\) levels. The functional relevance of NAD\(^+\) salvage from the dietary vitamin B3 precursor nicotinamide riboside (NR) via the rate limiting, muscle specific nicotinamide riboside kinase 2 (NRK2) enzyme is unclear, and could constitute an exploitable pathway for maintaining NAD\(^+\) levels with age. Using a novel in vivo skeletal muscle NRK2 overexpressing (NRK2.Tg) mouse model, this thesis determined that NRK pathway augmentation does not affect development or young metabolic phenotype, with no significant changes to the NAD\(^+\) metabolome or metabolic phenotype in aged animals with or without oral NR supplementation. These data further support evidence that the metabolic contribution of NRK mediated NAD\(^+\) salvage is dispensable in skeletal muscle. However, aged NRK2.Tg quadriceps, gastrocnemius and soleus muscles were significantly enlarged, suggesting resistance to sarcopenia. Aged NRK2.Tg myofibres presented with historic regeneration and perturbed NAD\(^+\) dependent cell-ECM adhesion processes, identifying the importance of localised NAD\(^+\) salvage via NRK2 for in vivo mammalian skeletal muscle remodelling.

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: Wellcome Trust
Subjects: Q Science > QP Physiology


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