Skeletal Muscle Mitochondrial and Cytosolic Metabolic Responses to Dietary and Genetic Manipulations

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Whitfield, Jamie

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University of Guelph


Skeletal muscle relies upon the catabolism of substrates via different metabolic pathways to produce ATP to support cellular function. Consequently, the regulation of these pathways during exercise is of great scientific interest. This thesis utilized nutritional and genetic models to manipulate skeletal muscle metabolism to gain a deeper understanding of the downstream implications on ATP production. The first study demonstrated that pyruvate dehydrogenase (PDH) contributed to metabolic inertia following consumption of a low-carbohydrate, high-fat (LCHF) diet during the transition from baseline to moderate-intensity cycling. These data are the first PDH measurements within the first 15 s of the work transition, and demonstrated that despite increases in intramuscular activators of PDH, the impairment seen at rest following a LCHF diet was maintained throughout exercise. In the second study, inorganic nitrate in the form of beetroot juice (BRJ) did not improve indices of mitochondrial bioenergetics despite decreasing whole-body O2 consumption during exercise. Mitochondrial efficiency and coupling were unaltered, and the expression of protein targets that could alter membrane potential or mitochondrial ADP supply was unchanged. In contrast, BRJ supplementation caused an increase in the propensity for mitochondria to produce H2O2. The third study examined changes in skeletal muscle contractile function to test whether the mechanism-of-action of BRJ is increased contractile efficiency. BRJ improved intrinsic muscle contractile properties, including rates of force development and relaxation, and increased force production at low stimulation frequencies. However, the causes of this improvement remain unclear, as cellular redox balance and the expression of proteins associated with calcium handling were unaltered. The final study utilized a novel genetic knockout model to explore the consequences of ablating the Rab GTPase-activating protein TBC1D1 on cellular homeostasis. It was demonstrated that TBC1D1 is required for contraction-, but not insulin-mediated GLUT4 translocation, and deletion of this protein decreases exercise tolerance. Consequently, these animals rely more on fatty acid oxidation, which may be supported by an increase in mitochondrial function. Altogether, this thesis provides novel insights into the control of skeletal muscle metabolism following nutritional and genetic interventions, and develops our understanding of the regulation of substrate provision and cellular energy production.



Mitochondria, Skeletal Muscle, Metabolism, Nitrates, Beetroot Juice, TBC1D1