NAD⁺/NADH and skeletal muscle mitochondrial adaptations to exercise

The pyridine nucleotides, NAD(+) and NADH, are coenzymes that provide oxidoreductive power for the generation of ATP by mitochondria. In skeletal muscle, exercise perturbs the levels of NAD(+), NADH, and consequently, the NAD(+)/NADH ratio, and initial research in this area focused on the contribution of redox control to ATP production. More recently, numerous signaling pathways that are sensitive to perturbations in NAD(+)(H) have come to the fore, as has an appreciation for the potential importance of compartmentation of NAD(+)(H) metabolism and its subsequent effects on various signaling pathways. These pathways, which include the sirtuin (SIRT) proteins SIRT1 and SIRT3, the poly(ADP-ribose) polymerase (PARP) proteins PARP1 and PARP2, and COOH-terminal binding protein (CtBP), are of particular interest because they potentially link changes in cellular redox state to both immediate, metabolic-related changes and transcriptional adaptations to exercise. In this review, we discuss what is known, and not known, about the contribution of NAD(+)(H) metabolism and these aforementioned proteins to mitochondrial adaptations to acute and chronic endurance exercise.