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The Impact of Exercise on the Regulation of Mitochondrial Content and Function in the Brain

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Title: The Impact of Exercise on the Regulation of Mitochondrial Content and Function in the Brain
Author: Herbst, Eric
Department: Department of Human Health and Nutritional Sciences
Program: Human Health and Nutritional Sciences
Advisor: Holloway, Graham
Abstract: The ability to combat mitochondrial dysfunction in neurodegenerative diseases with exercise is currently limited by our lack of understanding of the effects of exercise on brain mitochondria. Therefore, this thesis provides a series of investigations into the impact of acute and chronic exercise on altering mitochondrial content and function in the brain. Study one presents a method for permeabilizing small brain samples for analysis of mitochondrial respiration in situ. Analysis using the permeabilized brain preparation was characterized and compared against isolated mitochondria through assessing changes in respiration with acute ischemia-reperfusion injuries. Results demonstrated that the permeabilized brain preparation provides greater reliability while using less tissue and also maintaining the native mitochondrial reticulum. Study two of this thesis investigated the impact of acute exercise on stimulating traditional signalling kinases in the brain, as well as assessing changes to mitochondrial DNA, protein content, and respiration following chronic training. Results demonstrated that phosphorylation of AMPK, CAMKII, and P38 were not affected by acute exercise, where ERK1/2 phosphorylation was decreased versus controls. Further, no changes were observed in markers of mitochondrial content with chronic exercise training, suggesting mitochondrial biogenesis does not occur in the healthy brain with exercise. In study three, substrate-specific changes in mitochondrial respiration in the brain were assessed following acute exercise. Where pyruvate respiration was unaltered by exercise, glutamate respiration was enhanced as a result of changes in the malate- aspartate shuttle, identifying substrate-specific regulation of brain metabolism with exercise. Study four investigated the hypothesis that exercise could prevent symptoms and mitochondrial dysfunction in the brains of R6/1 Huntington’s disease mice. At 27 wks of age, mitochondrial protein content was impaired in the striatum with compensatory increases in mitochondrial respiration. With chronic exercise training, changes in mitochondrial content and respiration were prevented, identifying a beneficial effect of exercise in Huntington’s disease. Together, this work highlights that mitochondrial glutamate oxidation is stimulated by acute exercise, and that chronic exercise does not enhance mitochondrial content in the brains of healthy mice, but is capable of preventing the loss of mitochondrial content in mouse models of Huntington’s disease.
Date: 2015-06
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