Exploring the Physiological Effects of Altering NAD+ Biosynthesis in NMNAT Transgenic Mice
| Autor: | Lakeland, Thomas |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: |
NMN
Caloric restriction Nicotinamide mononucleotide 3214 Pharmacology and pharmaceutical sciences NMNAT3 NMNAT1 Fasting NAD Caloric modulation 3208 Medical physiology Nicotinamide adenine dinucleotide 3205 Medical biochemistry and metabolomics Nicotinamide mononucleotide adenylyl transferase Exercise |
| DOI: | 10.26190/unsworks/24920 |
| Popis: | Nicotinamide adenine dinucleotide (NAD), an archetypal cellular energy carrier, is vital to good health but declines with ageing and with metabolic disease. Restoration of declining NAD levels—achieved through diet, exercise, and pharmaceutical interventions—associates with increased longevity and a return to healthy physical function in various organisms. The aim of this thesis is to improve understanding of the therapeutic potential of the NAD+-synthesis enzyme nicotinamide mononucleotide adenylyl transferase (NMNAT) using mice that overexpress the nuclear and mitochondrial isoforms of this enzyme—NMNAT1 and NMNAT3, respectively. Firstly, we utilised different acute (24 h) states of feeding—fed, fasted, and post-fasting refed— to manipulate energetic stress and to induce metabolic defensive mechanisms. Modest differences in bodyweight in the ‘fed’ NMNAT1Tg/+ mice and in the ‘fasted’ NMNAT3Tg/+ mice suggest greater effects may be seen with chronic interventions; however, analysis of protein expression and fuel storage did not yield conclusive support for these effects. Secondly, a six-week progressive endurance training programme and testing protocol was used to provide an adaptive stimulus and to interrogate aerobic performance baseline and potential. Both transgenic lines of mice responded to exercise training similarly to their WT counterparts, displaying enhanced endurance and glucose tolerance. However, isoform-specific differences were identified in proteins and enzymes involved in glucose and lipid metabolism across different tissues. A third study was to be performed, utilising the NAD+-precursor nicotinamide mononucleotide (NMN) to provide substrate for maximum throughput of the enhanced NMNAT machinery, however, due to the COVID-19 pandemic these experiments were terminated before data could be generated. Standalone overexpression of NMNAT appears to have modest impact on metabolic profile and adaptation to energetic stress in healthy young mice, however, isoform-specific divergence in fuel handling and storage may be indicative of stronger effects in healthcompromised subjects. Future investigations combining NMNAT overexpression with additional NAD+-substrate and with metabolically compromised conditions will help to establish the therapeutic validity of NMNATs as a pharmacological target. |
| Databáze: | OpenAIRE |
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