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Investigating the Effect of NMNAT1 Overexpression on Skeletal Muscle Physiology and Metabolism

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  • Title:
    Investigating the Effect of NMNAT1 Overexpression on Skeletal Muscle Physiology and Metabolism
  • Author: Samsudeen, Azrah
  • Subjects: BIOMEDICAL AND CLINICAL SCIENCES
  • Description: NAD+ has long been an important molecule in cell metabolism for its redox activity in processes such as glycolysis, ATP production and lipid oxidation. In recent years NAD+ has also been recognised as an important substrate for enzymes including PARPs, sirtuins and ADP-ribosylases such as CD38 and CD157. As a result, NAD+ has been hailed as a key molecule in maintaining cell survival, and its concentrations directly impact key cellular processes such as cell metabolism, mitochondrial biogenesis, DNA damage repair, Ca2+signalling and lifespan. Given the wide array of functions mediated by NAD+, changing NAD+concentrations are often indicative of metabolic flux, with NAD+ levels consistently shown to decrease with ageing and metabolic disease, whereas exercise and caloric restriction increase cellular NAD+. The alteration of NAD+ levels via genetic manipulation, administration of precursors or inhibition of NAD+ consumers have all been shown to improve overall metabolic health and physiology across a variety of tissues and species, with increases to cellular NAD+levels increasing healthspan, extending lifespan and reversing the adverse impacts induced by high-fat feeding. The family of NMNAT enzymes involved in the final steps of NAD+biosynthesis present a unique opportunity for intervention in increasing NAD+ levels that is yet to be widely explored in the literature. Distinct subcellular localisation of NAD+ pools and NMNAT enzymes also suggest distinct functions for NAD+ in discrete intracellular organelles and sites. This thesis aimed to investigate the overexpression of NMNAT1 – the nuclear isomer of the NMNAT enzyme family and its impact on whole-body metabolism and ageing. Both whole-body and muscle-specific overexpression of NMNAT1 resulted in a significant reduction in skeletal muscle mass. Despite the marked decrease in muscle mass, NMNAT1 transgenic mice showed improved glucose tolerance, increased insulin sensitivity and uncompromised endurance capacity when challenged with exercise. These changes were also observed despite a paradoxical increase in skeletal muscle lipid content in NMNAT1 transgenic mice. NMNAT1 whole-body overexpression also showed some protective effects with regards to age-induced impairments to glucose tolerance and loss of muscle mass. These results indicate great potential for NMNAT1 in regulating whole-body metabolism in metabolically unfavourable conditions Source: TROVE
  • Creation Date: 2022
  • Language: English
  • Source: Trove Australian Thesis (Full Text Open Access)
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