Qi, Bo (2023) Impact of exercise training on stress signaling pathway and purine metabolism in healthy and disease models and the influence of ribose supplementation. PhD thesis, Victoria University.

Abstract

Regular exercise improves physical fitness and general health via significant muscle molecular adaptations. ATP (energy) and its regulation is critical to metabolic homeostasis. ATP hydrolysis and re-synthesis are typically balanced, disrupted when the rate of ATP re-phosphorylation can no longer support extreme exercise workload, such as high-intensity training (HIT), or production is compromised (metabolic disease). Consequently, purine degradation to terminal purine metabolites (hypoxanthine and xanthine) occurs, which diffuse across the sarcolemmal membrane into the blood converted to uric acid and eliminated by the kidneys. This process generates reactive oxygen species (ROS) that can damage skeletal muscle fibres and the local capillary network. Extreme metabolic insult triggers three possible responses: (1) oxidative stress; (2) endoplasmic reticulum (ER) instability; and (3) hypoxic stress. Cellular oxygen consumption and subsequent ROS production are implicit in the activation of these signaling pathways. ROS stimulates beneficial muscle adaptations associated with regular exercise as per the concepts of hormesis. However, overexposure (acute or chronic) can drive muscle dysfunction and pathology. Elucidation of the signaling pathways altered during intense metabolic stress, e.g. HIT or exercise in metabolically compromised muscle, is needed. Furthermore, supporting cellular metabolism under intense pressure could prevent excessive stress signaling and these negative consequences. Ribose supports purine recovery and biosynthesis, and supplementation may protect metabolically challenged muscles, or prevent formation of the critical signals required to induce beneficial adaptations within skeletal muscle, e.g., ROS. Study 1 examined the molecular stress signaling response to HIT in mice. Following HIT, the levels of Keap1, SOD, and PGC-1α were elevated in the skeletal muscles of female mice, yet the expression of HO-1, Sirt1 and PGC-1, which can be induced by hypoxic stress protein, HIF-1, was upregulated in male skeletal muscle. This indicates female skeletal muscle may be more responsive to oxidative stress, while male muscle may be more responsive to hypoxic stress. Study 2 examined (1) oxidative, metabolic and hypoxic stress signaling in metabolically challenged dystrophic (mdx) mouse model exposed to regular normo-tensive exercise; and (2) whether ribose supplementation could protect muscles from exacerbated myopathy. Ribose treatment enhanced resistance to fatigue and forelimb muscle strength in mdx mice by inducing hypoxia stress signaling. Additionally, we observed that ribose supplementation reduced purine degradation, leading to potential adaptations in ER stress signaling pathways by promoting fat metabolism. Therefore, ribose could be a therapeutic adjunct to treat muscle fatigue in DMD patients and female carriers of the dystrophin gene mutation. Study 3 focussed on exercise performance and stress signaling adaptations with HIT in humans. Impacted heavily by COVID-19, this small pilot study indicated that HIT training induces the Nrf2-mediated antioxidant program and Sirt1which may safeguard muscle cells against oxidative damage caused by exercise. This thesis examined models of stress in healthy and disease states to better metabolic signaling dynamic and influence of ribose supplementation on the adaptation pathways.

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