Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2016

Enhancing nuclear NAD+ via transgenic overexpression of the salvage enzyme NMNAT1 alters muscle fibre type and whole-body energy metabolism (#131)

Brenna Osborne 1 , Sanket Joshi 1 , Azrah Samsudeen 1 , Abhirup Das 2 , Corrine E Fiveash 1 , Lindsay E Wu 2 , Toshiyuki Araki 3 , David Sinclair 4 , Nigel Turner 1
  1. Mitochondrial Bioenergetics, Department of Pharmacology, UNSW, Kensington, NSW, Australia
  2. Molecular Biology of Ageing, Department of Pharmacology, UNSW, Kensington, NSW, Australia
  3. Peripheral Nervous System Research, National Institute of Neuroscience, NCNP, Tokyo, Japan
  4. Department of Genetics, Harvard Medical School, Boston, MA, USA

NAD+ is an essential cofactor known to regulate many metabolic pathways and physiological processes. Recently NAD+ metabolism has attracted much attention as a therapeutic pathway with potential to treat many different diseases. Nicotinamide mononucleotide adenylyltransferases (NMNATs) are enzymes of the NAD+ salvage pathway that convert nicotinamide mononucleotide (NMN) into NAD+. The nuclear NMNAT1 is thought to control NAD+ salvage in the nuclear compartment and may have important roles in modulating the activity of key NAD+ consuming enzymes such as sirtuins and PARPs.

Here we have examined the phenotype of male mice with whole-body transgenic overexpression of NMNAT1 (NMNAT1Tg) that were provided chow or high-fat diet (HFD) for 8 weeks. Compared to wildtype (WT), NMNAT1Tg mice showed a significant decrease in body weight, due to a marked reduction (30-40%) specifically in skeletal muscle mass, with no change in body length or other organ weights. NMNAT1Tg mice displayed higher energy expenditure (per kg lean mass) by whole-body calorimetry and were partially protected against HFD-induced glucose intolerance compared to WT when assessed by intraperitoneal glucose tolerance test (2g/kg lean mass). Interestingly, this improvement in glucose tolerance occurs despite an increase in quadriceps muscle triglyceride accumulation (+65% in NMNAT1Tg cf. WT, n=8, p<0.01). NMNAT1Tg also exhibit a functional decrease in forelimb grip strength (-15% in NMNAT1 cf. WT, n=6, p<0.01). The alterations in muscle size were linked to changes in fibre-type composition, with significant increases in mRNA for oxidative myosin heavy chain isoforms (MHC1, MHC2a, MHC2x), and a corresponding decrease in the fast-twitch MHC2b isoform.

Further investigation of the mechanism underlying these changes in muscle mass and muscle lipid may yield important insight into the role of metabolic changes induced by specific NAD+ pools within muscle cells.