Oral Presentation ANZOS-ASLM-ICCR 2019

Overexpression of an NAD+ biosynthesis enzyme alters skeletal muscle physiology and improves insulin action.  (#62)

Azrah F. Samsudeen 1 , Brenna Osborne 1 , Sarah E. Hancock 1 , Corrine E. Fiveash 1 , Amanda E. Brandon 2 , Abhirup Das 3 , Leonit Kiriaev 4 , David A. Sinclair 5 , Toshiyuki Araki 6 , Stewart L. Head 4 , Gregory J. Cooney 2 , Nigel Turner 1
  1. Mitochondrial Bioenergetics Laboratory, UNSW Sydney, NSW, Australia
  2. The Charles Perkins Centre, University of Sydney, NSW, Australia
  3. Molecular Biology of Ageing Laboratory, UNSW Sydney, NSW, Australia
  4. Department of Physiology, UNSW Sydney, NSW, Australia
  5. Harvard Medical School, Boston, USA
  6. National Center of Neuorology and Psychiatry, Tokyo, Japan

Nicotinamide adenine dinucleotide (NAD+) is a co-substrate for a multitude of biochemical reactions and reduced levels of NAD+ have been linked with metabolic dysfunction in ageing, obesity and diabetes. Our studies examined transgenic mice overexpressing nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) – a key regulator of NAD+ in the nuclear compartment of cells.

Transgenic mice (NMNAT1 Tg) and their wild-type littermates (WT) were administered a chow or high-fat diet (HFD) for 8 weeks to induce obesity and insulin resistance. In comparison to WT animals, NMNAT1 Tg mice exhibited no difference in fat accumulation but showed a decrease in lean mass on both diets, driven by a marked reduction (30-40%, p<0.001) in skeletal muscle mass. Immunohistochemical analysis showed the reduction in muscle size was due to a decrease in average fibre cross-sectional area, correlating with molecular changes that indicated a shift towards more oxidative muscle fibres, such as increased expression of myosin heavy chain isoforms (MHC) 1 and 2a and higher citrate synthase activity. Consistent with a shift to a more oxidative and less glycolytic (fast-twitch) phenotype in NMNAT1Tg vs. WT mice, forelimb grip strength was reduced in transgenic animals and isolated extensor digitorum longus and soleus displayed more oxidative twitch characteristics as well as improved force recovery after fatigue.

At the whole-body level, NMNAT1 Tg mice displayed higher energy expenditure, improved glucose tolerance and a greater clearance of glucose into skeletal muscle in hyperinsulinaemic-euglycaemic clamp experiments. Intriguingly, the improved insulin action occurred despite a marked accumulation of myocellular lipid. Overall, our findings suggest that enhancing nuclear NAD+ biosynthesis markedly alters skeletal muscle function and metabolism.