Influence of exercise training on nitric oxide pathways and their physiological effects

Nitric oxide (NO) is a critical signalling molecule in cardiovascular, metabolic, and muscular function. Endogenous NO production occurs via two primary metabolic pathways: 1) the classical nitric oxide synthases (NOS) pathway, and 2) the alternative (nitrate–nitrite–NO) pathway, in which inorganic nitrate (NO 3 - ) is sequentially reduced to nitrite (NO 2 - ) and other NO intermediates (e.g., S-nitrosothiol). The latter pathway relies heavily on the oral microbiota, which catalyze the two-electron partial reduction of NO 3 - to NO 2 - , which is influenced by oral physiology, microbial composition and salivary flow. While the role of exercise training in enhancing NOS-derived NO is well established, emerging evidence suggests that it may also augment NO bioavailability through the NO 3 - –NO 2 - –NO pathway. Furthermore, exercise training may influence the composition and functionality of oral microbiota, thereby indirectly modulating NO metabolism and oral health. However, the synergistic effects of exercise and oral microbiota on NO production remain underexplored. This review synthesises current evidence on how physical exercise may modulate both NO pathways and discusses the broader physiological implications. • The integrative effects of exercise on nitric oxide-producing pathways remain underexplored. • This review provides a comprehensive overview of how exercise enhances nitric oxide homeostasis. • Exercise training stimulates NO production through both nitric oxide synthase–dependent and nitrate–nitrite–nitric oxide pathways. • Exercise and dietary nitrate may exert synergistic effects on nitric oxide signalling. • The review discusses the broader physiological implications of these integrated mechanisms.