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The Influence of Exercise and High Fat Feeding on the Regulation of Mitochondrial Substrate Sensitivity in Skeletal Muscle

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Title: The Influence of Exercise and High Fat Feeding on the Regulation of Mitochondrial Substrate Sensitivity in Skeletal Muscle
Author: Miotto, Paula
Department: Department of Human Health and Nutritional Sciences
Program: Human Health and Nutritional Sciences
Advisor: Holloway, Graham
Abstract: This thesis consists of a variety of studies using physiological, molecular, and chemical approaches to identify novel regulation of skeletal muscle mitochondrial lipid and ADP sensitivity in response to exercise and a high fat (HF) diet. This thesis also examined the biological importance of substrate sensitivity and mitochondrial reactive oxygen species (ROS) within the context of exercise adaptations and insulin-resistance. In study 1, wild-type and muscle-specific AMPK wild-type and knockout mice were used to determine whether the intermediate filaments regulate CPT-I sensitivity for malonyl-CoA (M-CoA) inhibition. Chemical disruption or exercise resulted in less M-CoA inhibition independent of changes in the sensitivity of other substrates (pyruvate, ADP, palmitoyl-carnitine) in an AMPK-independent manner, suggesting a similar mechanism to support increased fatty acid oxidation during exercise. In study 2, mitochondrial creatine kinase (Mi-CK) wild-type and knockout mice were used to examine the importance of this enzyme in augmenting ADP transport and maintaining energy homeostasis during exercise. In contrast to wild-type mice that had reduced ADP sensitivity during exercise, ablation of Mi-CK improved ADP sensitivity independent of changes in exercise tolerance or metabolic profiles. These data suggest that Mi-CK is not required for ADP transport during exercise due to external regulation of VDAC/ANT. In study 3, the Mi-CK mouse strain was used to determine the biological importance of reductions in ADP sensitivity during exercise. Exercise resulted in lower mitochondrial ADP sensitivity, an impaired ability for ADP to suppress ROS, and increased mitochondrial biogenesis acutely (PGC-1α, PGC-1, PDK4) and chronically (complexes I-IV of the electron transport chains) in wild-type mice. In contrast, these responses were completely attenuated in Mi-CK knockout mice after acute exercise and chronic training. In study 4, consumption of a HF diet was used to determine the role of mitochondrial ADP sensitivity and ROS emission as a cause of mitochondrial dysfunction. HF consumption impaired ADP-stimulated respiration and sensitivity, impaired ADP suppression of ROS, and lowered carboxyatractyloside-mediated inhibition on ANT that was amplified by P-CoA concentrations that reflect skeletal muscle. Overall, this thesis provides novel insight into the regulation of mitochondrial lipid and ADP sensitivity through CPT-I and the VDAC/ANT axis.
URI: http://hdl.handle.net/10214/14064
Date: 2018-08
Rights: Attribution-NonCommercial-NoDerivs 2.5 Canada


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Attribution-NonCommercial-NoDerivs 2.5 Canada Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivs 2.5 Canada