Increased nuclear NAD+ biosynthesis alters skeletal muscle physiology

Samsudeen AF1, Fiveash CE1, Brandon AE2, Das A3, Kiriaev L4, Araki T5, Head SI4, Cooney GJ2, Osborne B1 and Turner N1

  1. Mitochondrial Bioenergetics Laboratory, UNSW Sydney.
  2. The Charles Perkins Centre, University of Sydney.
  3. Molecular Biology of Ageing Laboratory, UNSW Sydney.
  4. Department of Physiology, UNSW Sydney.
  5. National Center of Neurology and Psychiatry, Tokyo, Japan.

Nicotinamide adenine dinucleotide (NAD+) is a ubiquitous co-substrate used in a multitude of cellular reactions. Recent recognition of the role of NAD+ in obesity and ageing has sparked a surge in interest in NAD+ biology. Nicotinamide mononucleotide adenylyltransferase (NMNAT) is a key enzyme regulating NAD+ levels, however the metabolic consequences of NMNAT manipulation has not been explored. Our studies investigated transgenic mice overexpressing NMNAT1 (the nuclear NMNAT isoform) where NMNAT1Tg mice had a reduced lean mass compared to wild-type (WT) littermates, primarily driven by a marked reduction (~30-40%) in skeletal muscle mass. Functionally, NMNAT1Tg mice showed reduced forelimb grip strength in comparison to WT littermates, but surprisingly no difference in exercise endurance. Immunohistochemical analysis showed a decrease in the average cross-sectional area of muscle fibres underpinned the reduced muscle mass. NMNAT1Tg muscle was characterised by an increase in more oxidative myosin heavy chain (MHC) isoforms (MHC1, MHC2a) and decreased fast-twitch MHC2b expression. A potential shift to a more oxidative phenotype in NMNAT1Tg vs. WT mice was confirmed by twitch characteristics and force/fatigue experiments in isolated extensor digitorum longus and soleus muscles. At a whole-body level, NMNAT1Tg mice showed higher energy expenditure, improved glucose tolerance and greater clearance of glucose into skeletal muscle in hyperinsulinaemic-euglycaemic clamp experiments. Overall, our findings indicate that enhancing nuclear NAD+ biosynthesis invokes widespread changes in skeletal muscle physiology.