NAD⁺ centric mechanisms and molecular determinants of skeletal muscle disease and aging

The nicotinamide adenine dinucleotide (NAD⁺) is an essential redox cofactor, involved in various physiological and molecular processes, including energy metabolism, epigenetics, aging, and metabolic diseases. NAD⁺ repletion ameliorates muscular dystrophy and improves the mitochondrial and muscle stem cell function and thereby increase lifespan in mice. Accordingly, NAD⁺ is considered as an anti-oxidant and anti-aging molecule. NAD⁺ plays a central role in energy metabolism and the energy produced is used for movements, thermoregulation, and defense against foreign bodies. The dietary precursors of NAD⁺ synthesis is targeted to improve NAD⁺ biosynthesis; however, studies have revealed conflicting results regarding skeletal muscle-specific effects. Recent advances in the activation of nicotinamide phosphoribosyltransferase in the NAD⁺ salvage pathway and supplementation of NAD⁺ precursors have led to beneficial effects in skeletal muscle pathophysiology and function during aging and associated metabolic diseases. NAD⁺ is also involved in the epigenetic regulation and post-translational modifications of proteins that are involved in various cellular processes to maintain tissue homeostasis. This review provides detailed insights into the roles of NAD⁺ along with molecular mechanisms during aging and disease conditions, such as the impacts of age-related NAD⁺ deficiencies on NAD⁺-dependent enzymes, including poly (ADP-ribose) polymerase (PARPs), CD38, and sirtuins within skeletal muscle, and the most recent studies on the potential of nutritional supplementation and distinct modes of exercise to replenish the NAD⁺ pool.