The effect of exercise and nutritional interventions on promoting adaptations to redox signalling

Redox signalling refers to the often reversible modification of molecules by reactive oxygen and nitrogen species (RONS) and electrophilic molecules. Collectively, redox signalling regulates a multitude of important physiological processes. One pathway highly inducible to the signalling potential of RONS and electrophiles is the nuclear factor erythroid 2-related factor (NRF2) pathway. NRF2 is a transcription factor which, amongst other roles, regulates endogenous antioxidative defence systems. Antioxidant defence involves a wide range of enzymatic and non-enzymatic molecules that safeguard against excessive RONS production. When RONS production outweighs antioxidant defence systems, unspecific damage to molecules may, if left unresolved, lead to the pathogenesis of numerous diseases and possibly accelerate ageing.

Numerous clinical trials have tested whether pharmacological interventions that purportedly activate NRF2 can treat disease marked by a prolonged, chronic imbalance between RONS and antioxidants, a state termed oxidative distress. While several pharmacological interventions can modulate NRF2 activity, adverse side effects have been documented. Non pharmacological lifestyle interventions such as physical exercise and (poly)phenols, bioactive molecules derived from foods, could offer a cheaper and safer alternative method of augmenting NRF2.

Due to the chemical structure of the NRF2 system, there is also rationale to suggest that exercise and (poly)phenols could act synergistically to activate NRF2, amplifying the biological responses regulated by NRF2. There is little data, however, to show that exercise alone or combined with (poly)phenol interventions sufficiently activate NRF2; moreover, there are currently no studies in humans examining the potential additive effects of these lifestyle interventions on NRF2 signalling; thus, further research is required to understand this. Furthermore, sex differences in redox signalling have been reported in rodents, however, it is unknown whether these disparities translate into humans; if so, this may result in sex27 specific variations in NRF2 activity and redox adaptations. Accordingly, the experimental Chapters presented in this thesis explored the effects of exercise, exercise with (poly)phenol supplementation, and sex, on NRF2 activity in healthy, human participants.

Chapter 3 investigated the effects of eccentric-heavy exercise and combined with 6 d supplementation of green tea, a popular therapeutic beverage abundant in (poly)phenols, on NRF2 activity in healthy male participants. This study observed that eccentric exercise alone, and exercise combined with green tea, had no significant effect on NRF2 activity; however, exercise did elevate the enzymatic activity of the NRF2 gene target glutathione reductase.

Chapter 4 aimed to expand on the question of whether eccentric-heavy exercise, performed with a greater sample size than that recruited in Chapter 3, enhances NRF2 activity in healthy males compared to a non-exercise control group. This study demonstrated that NRF2 activity was greater immediately post- and 1 h post-exercise compared to the same time points under resting conditions. NRF2 activity was also significantly greater at 1 h post-exercise compared to immediately post-exercise.

41 Chapter 5 returned to examine the synergistic application of eccentric exercise with a different (poly)phenol, this time curcumin, a (poly)phenol rich source derived from the turmeric spice, on NRF2 activity in healthy males and females. This study reported that strenuous plyometric-type exercise with and without curcumin supplementation for 4 d failed to augment NRF2 activity; however, curcumin supplementation appeared to increase glutathione peroxidase activity and decrease circulating neutrophil concentrations.

Chapter 6 focused on examining whether there are differences in basal and exercise-induced NRF2 activity between males and females. This study reported that males and females had similar NRF2 responses at rest and up to 1 h post exercise. There were some sex-specific divergences, however, for inflammatory markers (interleukin-6, tumour necrosis factor-alpha, and neutrophil concentrations), which were unlikely to be mediated by NRF2.

Collectively, the findings presented in this thesis indicate that performing eccentric exercise could be a viable therapeutic strategy in elevating NRF2 activity in some individuals; however, its synergistic activation with (poly)phenols does not amplify the exercise-induced activity of this transcription factor, at least in peripheral blood mononuclear cells. While these studies were with healthy young individuals, the findings in this thesis suggest, although the effect is evidently small, exercise could be used as a therapeutic intervention to activate NRF2 in humans; however, future studies are required that employ greater sample sizes to account for the small differences and large variability observed in exercise-induced NRF2 activity.