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NMNAT1 overexpression alters skeletal muscle physiology and improves glucose metabolism in aged mice

Azrah Samsudeen (1), Brenna Osborne (1), Sarah Hancock (1), Corrine Fiveash (1), Amanda Brandon (2), Abhirup Das (3), Leonit Kiriaev (4), David Sinclair (3, 5), Toshiyuki Araki (6), Stewart Head (4), Gregory Cooney (2) and Nigel Turner (1)

  1. Mitochondrial Bioenergetics Laboratory, UNSW Sydney, New South Wales, Australia

  2. The Charles Perkins Centre, University of Sydney, New South Wales, Australia

  3. Molecular Biology of Ageing Laboratory, UNSW Sydney, New South Wales, Australia

  4. Department of Physiology, UNSW Sydney, New South Wales, Australia

  5. Harvard Medical School, Boston, USA

  6. National Center of Neurology and Psychiatry, Tokyo, Japan

Nicotinamide adenine dinucleotide (NAD+) is a co-substrate for a multitude of biochemical reactions. As significant decreases in NAD+ levels have been linked with metabolic dysfunction in ageing, obesity and diabetes, our studies investigate transgenic mice overexpressing nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) – a key enzyme in the biosynthesis of NAD+ in the nuclear compartment of cells. Our findings show that transgenic mice (NMNAT1Tg) exhibited a significant decrease in lean mass compared to wild-type (WT) littermates with no difference in fat mass. This decrease in lean mass was driven by a significant reduction (30-40%, p<0.001) in skeletal muscle mass. Previous studies showed the reduction in muscle size to be a result of decreased average fibre cross-sectional area, correlating with changes observed at the level of mRNA where NMNAT1Tg skeletal muscle expressed higher levels of myosin heavy chain isoforms (MHC) 1 and 2a in comparison to WT tissue. In combination with higher citrate synthase activity, a shift towards more oxidative muscles in NMNAT1 Tg mice is observed.

Functionally, an oxidative shift was evident in force-fatigue experiments where NMNAT1Tg extensor digitorum longus and soleus muscles to be able to improve recovery after fatigue. At the whole-body level, NMNAT1Tg mice displayed higher energy expenditure and improved glucose tolerance including a greater clearance of glucose into skeletal muscle in hyperinsulinaemic-euglycaemic clamp experiments despite an increase in myocellular lipid in NMNAT1Tg skeletal muscle. Our studies further investigated NMNAT1Tg mice aged 6-24 months where NMNAT1Tg mice consistently showed improved glucose handling compared to WT littermates. Whilst there was a decline in endurance capacity across both genotypes with age, NMNAT1Tg mice did not show a deficit in endurance compared to WT littermates at each age. Overall, our findings suggest that enhancing nuclear NAD+ via NMNAT1 overexpression alters skeletal muscle physiology and whole-body metabolism.