The Effect of Inorganic Nitrate on Exercise Capacity and Metabolism in Health and Disease

Nitric Oxide (NO) is a key signaling molecule involved in various physiological processes, including vasodilation, mitochondrial function, muscle contraction, glucose and calcium homeostasis, and fatigue resistance during exercise. It is now widely recognized that reduced NO bioavailability is associated with the development and presence of cardiovascular and metabolic diseases and is a contributing factor in exercise intolerance. Inorganic dietary nitrate (NO3-) has become a broadly used supplement to increase or restore NO bioavailability in health and disease, respectively. The supplementation response during exercise varies between individuals of different health statuses and fitness statuses, and it is also dependent on the dose and supplementation regime. However, the role of sex on the effect of NO3- supplementation in exercise outcomes has not been determined. Thus, the focus of the first two manuscripts was to determine the role of sex in the effects of NO3- supplementation on different exercise outcomes. The focus of Manuscript 1 (Chapter 2) was to explore the role of sex and NO3- supplementation on exercise economy and exercise capacity during moderate-intensity exercise and severe-intensity exercise, respectively. Despite seeing elevations in plasma NO3- and NO2- concentrations after the ingestion of NO3- supplementation in both sexes, only males seem to benefit from supplementation. While females showed no improvement in exercise economy during a submaximal cycle ergometer test, males showed a ~6% reduction in oxygen consumption at the same power output. Males also showed improvements in exercise capacity during a time-to-exhaustion trial within the severe exercise domain. Taken all together, NO3- supplementation seems to benefit males but not females during exercise modalities that rely on the cardiovascular system. The objective of Manuscript 2 (Chapter 3) was to determine the role of sex in NO3- supplementation on skeletal muscle function and fatigue resistance. During skeletal muscle contractile function, NO3- supplementation seems to have differentiated effects in males and females. Males seem to benefit from NO3- supplementation during maximal isokinetic knee extension as the contraction velocity tested increases. Females, on the other hand, showed a detrimental effect on contractile function measured during isokinetic knee extension and when maximal knee extension power (Pmax) and velocity (Vmax) are estimated. Both sexes showed no improvement on a fatigue resistance protocol. Based on our results, using NO3- supplementation as an ergogenic in females should be viewed with caution, and warrants further investigation.
Manuscript 3 (Chapter 4) focuses on NO3- supplementation as an exercise therapeutic rather than an exercise enhancer in individuals with cardiovascular disease (CVD). Specifically, individuals with peripheral arterial disease (PAD), which is a disease characterized by diminished vascular NO production, has shown to increase exercise capacity and improve symptoms during walking (i.e. longer pain-free walking). However, the underlying mechanisms are not fully understood. Thus, the objective of Manuscript 3 (Chapter 4) was to explore the effect of NO3- supplementation on skeletal muscle bioenergetics and tissue perfusion of the calf muscles after peak plantar flexion exercise in patients with PAD. After following NO3- supplementation, patients with PAD showed a significant increase in circulating plasma NO2-. This was accompanied by an increase in claudication-free walking but not peak walk time. Advanced MRI techniques allowed us to assess the effect of NO3- supplementation on tissue perfusion and metabolism of skeletal muscle during peak plantar flexion exercise. We found that after supplementation, tissue perfusion increases, and oxidative metabolism is improved. All together suggests that NO3- supplementation may be acting as a therapeutic in this clinical population, restoring tissue perfusion and metabolism during exercise, as such, improving patients’ symptoms during walking.