Date of Award:
Master of Science (MS)
David A. York
The Endoplasmic Reticulum (ER) is a net-like intracellular organelle where protein is folded, matures, and is transported. When cellular stressful circumstances affect the ER, unfolded proteins are stacked in the ER lumen. This cellular stress is called ER stress. To defeat ER stress, cells have a defensive mechanism called the Unfolded Protein Response (UPR). Many chronic diseases such as obesity and type 2 diabetes or neurodegenerative disease such as Alzheimer’s disease have recently been linked to ER stress. Exercise has a significant effect on ameliorating the development of these chronic diseases or neurodegenerative diseases. However, no studies have assessed the effect of exercise on UPR activity in the brain. So this study was mainly focused on identifying how voluntary running wheel exercise affects the UPR in the brain of C57BL/6 mice exposed to a variety of dietary conditions of differing levels of dietary fat and different periods of feeding. As an exercise protocol, access to a voluntary running wheel for 3 weeks was used and running mice were grouped depending on their level of running activity. Using real-time PCR and western blotting, UPR-related gene/protein expression (XBP1, ATF6, eIF2α, and GRP78) was assessed in different brain regions. Exercise had a significant effect on up-regulating UPR activity in the brain of mice fed low fat diet (LFD) or high fat diet (HFD) for 3 weeks or 3 months. These effects were time and brain region dependent. However, the effect of exercise on up-regulating UPR disappeared in mice fed very high fat diet (VHFD) for 4 months. In addition to assessing UPR activity, the possibility that exercise-induced UPR activation was associated with activation of apoptosis was investigated. Apoptotic signaling was not affected by exercise. Trophic factors are activated by exercise and are known to be linked to UPR activity. The possibility that IGF-1, one such trophic factor, was responsible for exercise-induced UPR up-regulation without activating apoptosis was studied. The results showed that IGF-1 was not responsible for exercise-related activation of the UPR in the brain. The chemical chaperone 4-phenylbutyric acid (PBA) was given to mice to reduce ER stress and the effect of exercise on the UPR of the brain was studied. PBA had a tendency to lower ER stress in the hypothalamus. In this condition, exercise had a significant effect to decrease UPR activity. In conclusion, voluntary exercise activates the UPR in several brain regions of mice exposed to high-fat diet for up-to 3 months without activating apoptotic signaling. Only long-term exposure to dietary fat increased the brain UPR. It is possible that this exercise-induced UPR activation without apoptosis may contribute to the protective effect of exercise on brain health. (134 pages)
Kim, Yu Ho, "Effect of Voluntary Exercise and Diet on the Unfolded Protein Response in the Brain of Mice" (2011). All Graduate Theses and Dissertations. 1114.
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