Mammalian skeletal muscle is a highly dynamic organ capable of structural and metabolic remodeling in response to exercise demands, nutrient supply, and environmental insults. Muscle also plays a central role in the maintenance of whole-body energy balance, capable of both storing and oxidizing carbohydrate and lipid fuels. The course of natural aging leads to a gradual decline in the mass, strength, and oxidative capacity of skeletal muscle, which increases the susceptibility of the elderly to frailty and metabolic diseases, such as Type II Diabetes. Ectopic muscle lipids can also exacerbate the metabolic complications of obesity, prompting interest in new means of combating this effect by stimulating aerobic muscle metabolism. Several lines of evidence have converged on the fundamental electron-shuttling metabolite, nicotinamide adenine dinucleotide (NAD), as a co-factor and signaling intermediate uniquely positioned to modulate whole-body energy balance through transcriptional and post-translational mechanisms. Though it has long been known that NAD supports essential metabolic pathways in muscle, attempts to stimulate oxidative metabolism by systemically increasing intracellular NAD concentration have been unable to resolve the specific contribution, if any, of skeletal muscle to the resulting phenotypes. Furthermore, the observation that muscle NAD content tends to decline with age has never been demonstrated to have functional consequences. I have addressed these questions experimentally by generating transgenic mice with altered muscle expression of nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in the mammalian NAD salvage biosynthetic pathway. Despite effectively increasing the muscle NAD pool, Nampt expression alone is not sufficient to stimulate mitochondrial function in young mice and provides no protection from diet-induced obesity. However, aging these mice for 24 months revealed partial preservation of youthful exercise capacity through primarily non-transcriptional mechanisms. Specific deletion of Nampt in adult mice elucidated a critical threshold of NAD required to maintain the exercise performance, as well as the mass and strength of muscle, by directly supporting aerobic ATP synthesis. Importantly, these parameters can be rapidly and uniformly restored by administration of the NAD precursor, nicotinamide riboside. These studies indicate that loss of NAD homeostasis is a reversible cause of skeletal muscle dysfunction with wide- ranging therapeutic implications.