| Summary: | The body's carnitine pool is almost entirely confined to skeletal muscle where it plays a dual role in cellular energy metabolism. At rest and during moderate intensity exercise, carnitine is an obligatory cofactor in long chain fatty acid metabolism, whereas during intense contraction, carnitine plays a central role in the maintenance of the mitochondrial free Co enzyme A (CoASH) pool. Although carnitine supplementation has been touted as a means to alter skeletal muscle fuel metabolism for several decades, only recently has it been shown that skeletal muscle carnitine availability can be elevated in humans, and that this leads to alterations in muscle fuel metabolism, a finding which has led to renewed interest in carnitine as a regulator of skeletal muscle fuel metabolism. Despite recent developments in our understanding of the physiological impact of skeletal muscle carnitine loading, little is known regarding the metabolic impact of carnitine depletion on skeletal muscle fuel metabolism. The first objective of the work presented in this thesis was to establish a rodent model of skeletal muscle carnitine depletion. This was achieved via oral supplementation with mildronate, a compound which has been shown to attenuate carnitine biogenesis, while also accelerating its renal clearance of carnitine in vivo. Thereafter, the impact of skeletal muscle carnitine depletion on whole body and skeletal muscle fuel metabolism was investigated in non-obese and obese, insulin resistant rodents. Collectively, the experiments detailed in this thesis offer a novel insight regarding the metabolic consequences of skeletal muscle carnitine depletion. More specifically, mildronate administration resulted in a significant reduction in skeletal muscle total carnitine content, which was largely attributable to a near complete depletion of the muscle free carnitine pool. This resulted in a reduction in muscle long chain acylcarnitine content, indicative of impaired carnitine palmitoyl transferase 1 (CPTl) flux and mitochondrial long chain fatty acid transport. Indeed, skeletal muscle carnitine depletion attenuated fat oxidation in both non-obese and obese insulin resistant rodents. In addition to a marked reduction in fat oxidation, carnitine depletion also resulted in an increase in skeletal muscle glycogen utilisation, an effect which was more apparent in obese insulin resistant rodents when compared to non-obese rodents. Interestingly, an additional novel finding of this work was the fact that despite driving skeletal muscle glycogenolysis, skeletal muscle carnitine depletion impaired glucose tolerance in obese insulin resistant rodents. This finding is most likely a result of hepatic lipid accumulation and a subsequent reduction in hepatic insulin sensitivity. Taken together, the data presented in this thesis clearly demonstrates that skeletal muscle carnitine depletion attenuates CPTl flux and fat oxidation while driving skeletal muscle CHO oxidation. However, despite increased glycogenolysis in carnitine depleted skeletal muscle, carnitine depletion does not improve glucose tolerance in obese insulin resistant rodents, and therefore would not be a suitable intervention to manage hyperglycaemia in diabetic subjects.
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