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Increasing nuclear NAD+ biosynthesis alters skeletal muscle size and metabolism

B. Osborne,1 A. Samsudeen,1 S. Joshi,1 A.E. Brandon,2,3 C.E. Fiveash,1 L. Kiriaev,4 B. Wilkins,1 L.E. Wu,5 A. Das,5 T. Araki,6 P. Gregorevic,7 S.I. Head,4 D.A. Sinclair,5,8 G.J. Cooney2,3 and N. Turner,1 1Mitochondrial Bioenergetics Laboratory, School of Medical Sciences, UNSW, NSW 2052, Australia, 2Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia, 3The Charles Perkins Centre, University of Sydney, NSW 2006, Australia, 4Cellular and Systems Physiology Laboratory, School of Medical Sciences, UNSW, NSW 2052, Australia, 5Molecular Biology of Ageing Laboratory, School of Medical Sciences, UNSW, NSW 2052, Australia, 6National Institute of Neuroscience, Tokyo, Japan, 7Muscle Research and Therapeutics, Baker Heart and Diabetes Institute, Melbourne VIC 3004, Australia and 8Paul F. Glenn Center for the Biological Mechanisms of Aging, Harvard Medical School, Boston, MA 02115, USA.

Nicotinamide adenine dinucleotide (NAD+) is a ubiquitous metabolite involved in a multitude of reactions throughout the cell. The recent recognition that NAD+ levels influence many processes in obesity and ageing has sparked a surge in interest in NAD biology. Nicotinamide mononucleotide adenylyltransferase (NMNAT) is a key enzyme of the NAD+ salvage pathway, that catalyses the conversion of NAD+ precursors to NAD+, thus playing a major role in maintaining cellular NAD+ concentrations. However little is known about the metabolic role of NMNATs or how changing NAD+ levels via NMNAT manipulation alters metabolism.

In the current study we have examined transgenic mice overexpressing NMNAT1 (a NMNAT isoform residing in the nuclear compartment). Transgenic mice (NMNAT1Tg) and their wild-type littermates (WT) were administered a chow or high-fat diet (HFD) for 8 weeks, with NMNAT1Tg mice exhibiting no difference in fat accumulation, but a decreased lean mass on both diets, primarily as a result of a pronounced reduction (30-40%, P<0.001) in skeletal muscle mass. Immunohistochemical analysis of laminin-stained sections showed the reduced muscle size in NMNAT1Tg mice was due to smaller individual muscle fibres. Assessment of the mRNA expression of myosin heavy chain (MHC) isoforms indicated an oxidative shift in skeletal muscle, with a significant increase (P<0.05) in more oxidative MHC isoforms (MHC1, MHC2a), accompanied by a decrease (P<0.01) in fast MHC2b expression.

At the whole-body level, NMNAT1Tg mice displayed higher energy expenditure and improved glucose tolerance (ipGTT p<0.01) on both diets. When subjected to hyperinsulinaemic-euglycaemic clamps, NMNAT1Tg mice showed an increased whole-body glucose infusion rate (P<0.05), with a significantly elevated (40-80%, P<0.05) clearance of glucose into various skeletal muscles.  

Overall our findings suggest that increasing NAD+ biosynthesis in the nucleus has a profound influence on muscle size and metabolism, with further studies required to understand the molecular pathways and mechanisms involved.