Exploring how compartment‐specific changes in NAD biosynthesis influence the response to endurance training

Abstract

Nicotinamide adenine dinucleotide (NAD) plays a vital role in the maintenance of health and is known to decline with ageing and with metabolic and chronic disease states. Restoration of declining NAD levels—which can be achieved through diet, exercise, and pharmaceutical-based interventions—has been demonstrated in various organisms to associate with increased longevity and a return to healthy physical function. Our group has previously observed alterations in metabolic processes and in muscle morphology in mice overexpressing the NAD biosynthetic enzyme nicotinamide mononucleotide adenylyl transferase (NMNAT) to target nuclear (NMNAT1) and mitochondrial (NMNAT3) NAD upregulation. In the present investigation, both NMNAT1 and NMNAT3 mice and their respective wildtype littermates were exposed to a six-week progressive endurance training programme. Endurance capacity, oral glucose tolerance (oGTT), various measures of circulating and tissue lipid and glucose content, and skeletal muscle protein expression were assessed. Despite substantially reduced muscle mass in the NMNAT1Tg/+ group and lower overall performance in the NMNAT3Tg/+ group, the ability to adapt to exercise training was not diminished in either group (improvement above baseline of 147.7 ± 40.1% and 136.6 ± 28.6% for NMNAT1 TG and WT, respectively; and 98.4 ± 36.1% and 72.3 ± 20.5% for NMNAT3 TG and WT, respectively; n = 8-9). NMNAT1 overexpression was associated with signs of altered glucose handling, including increased storage of glycogen in liver and quadriceps, but little evidence for altered lipid handling was present. NMNAT3 overexpression, by contrast, did not present with any alterations in glucose metabolism or glycogen storage, but did result in reductions in serum, liver, and heart triglycerides within sedentary but not trained animals. Our results suggest that, despite alterations in glucose and lipid handling, overexpression of NMNAT in the nucleus or the mitochondria does not result in a reduced capacity for adaptation to endurance training. NMNAT overexpression within the nucleus appears to positively impact glucose metabolism; whereas overexpression within the mitochondria appears to alter lipid metabolism in sedentary animals, and these differences diminish with exercise training.