Increased nuclear NAD+ biosynthesis alters skeletal muscle physiology
- Mitochondrial Bioenergetics Laboratory, UNSW Sydney.
- The Charles Perkins Centre, University of Sydney.
- Molecular Biology of Ageing Laboratory, UNSW Sydney.
- Department of Physiology, UNSW Sydney.
- 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.