Zarekookandeh, Navabeh (2024) Exercise and neuroprotection: the effects of exercise intensity on muscle-derived mediators of neuroprotection in middle-aged adults and mice. PhD thesis, Victoria University.

Abstract

Exercise as a medical intervention is effective to prevent and manage many chronic and complex diseases, including dementia. Regular aerobic exercise has been shown to protect against age-related brain atrophy and decrease the likelihood of cognitive decline. The mechanisms through which exercise provides a neuroprotective effect are yet to be fully elucidated, but may be related to a maintenance of brain volume and neuronal survival, improved cerebrovascular density and function, and/or increased synaptic plasticity. In addition, there is growing evidence to suggest the beneficial effects of exercise on brain health and cognitive function are, at least in part, mediated by factors released by skeletal muscle during contraction. The fact that the brain responds to exercise suggests that muscle-derived peripheral factors, or “myokines”, may play a key role in muscle-brain crosstalk and exercise neuroprotection. However, the most effective ‘dose’ of aerobic exercise to promote beneficial changes in these myokine pathways is currently unknown. Specifically, most of the evidence to date is from studies that have used moderate-intensity exercise, and research investigating the merit of high-intensity exercise is scarce. Considering the well-established role of high-intensity interval training (HIIT) in protecting against numerous medical conditions, more research is needed to identify the most effective ‘dose’ of exercise to improve the beneficial effects of these myokines. In the subsequent experimental chapters, I investigated the impact of exercise intensity on myokine pathways, exploring their dynamics in muscle and blood in middle-aged human and animal models. Additionally, this thesis also investigated the intricate relationship between exercise intensity and molecular adaptations within the brain using an animal model. In Chapter Four, the effects of exercise intensity on mitochondrial function in sedentary middle-aged adults were explored. High-Intensity Interval Training, was observed to be more effective in increasing cardiorespiratory fitness (V̇O2peak) as compared with Moderate-Intensity Continuous Training (MICT). Both exercise intensities induced similar skeletal muscle mitochondrial adaptations, suggesting that the cognitive benefits mediated by muscle mitochondria may be similar between MICT and HIIT. Chapter Five explored the implications of exercise intensity on muscle-derived mediators of neuroprotection in middle-aged adults. While HIIT enhanced aerobic fitness to a greater degree than MICT, both intensities induced similar changes in skeletal muscle myokine content. Regarding the Kynurenine pathway, improvements were observed in both training groups, which were augmented in the HIIT group for certain muscle (kynurenine aminotransferase1) and blood (Kynurenic acid and Picolinic acid) markers. In Chapter Six, the role of exercise intensity on neuroprotective markers were investigate in muscle, blood, and brain tissues of exercised mice. A number of tissue-specific responses to exercise intensity were observed in this chapter, notably, differential regulation of the Kynurenine pathway, as well as mitochondrial respiration, in the brain as compared with muscle and blood. Despite these changes, Adult Hippocampal Neurogenesis and associated behavioural parameters remained unchanged in both groups. Collectively, these results underscore the complexity of exercise-induced molecular responses impacting the brain, and highlight the need for a comprehensive approach to understanding the impact of exercise and its dose on cognitive function. The results, contrary to the hypothesis, indicate that high-intensity exercise is as effective as moderate-intensity exercise in regulating neuroprotective myokine pathways. In conclusion, this thesis provides valuable insights into the multifaceted effects of exercise intensity on neuroprotective mechanisms, emphasising the need for further research to refine exercise prescriptions for improving brain health and cognitive function.

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