Magnetic Resonance Spectroscopy of creatine-related energy metabolism in skeletal muscle and brain.
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RU Radboud Universiteit Nijmegen, 10 oktober 2005
Promotores : Heerschap, A., Wieringa, B.
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SubjectUMCN 5.3: Cellular energy metabolism
Magnetic Resonance Spectroscopy (MRS) is a powerful technique to study transgenic animals in vivo, in particular when substrates of the enzymes involved show signals in the MR spectra. This thesis focuses on the role of creatine kinase (CK) and adenylate kinase (AK) in a number of strongly interconnected energetics pathways, i.e. the creatine (Cr)-CK system, the AK system, glycolysis, the mitochondrial TCA cycle and oxidative phosphorylation. Disabling one or more enzymes may lead to rerouting of fluxes through the remaining energy pathways. First, a study on postnatal development of mice lacking CK in muscle was performed to gain insight into the origin of the phosphocreatine signal that was somewhat unexpectedly observed in earlier studies of mice with complete CK deficiency. Furthermore, we studied energy provision in muscle of mice with a combined CK and AK deletion during an ischemic challenge and upon recovery. Comparing the results of this study with similar studies in cytosolic muscle-CK and AK single knock-out mice gives a new perspective on the interaction between the CK and AK enzyme systems in vivo. To study whether CK absence in brain also results in an up-regulation of glycolysis, similar to the situation in muscle, 13C MRS techniques were developed which were applied to mice that lack CK in the brain. Using 13C MRS, we compared conversion of glucose, formation of lactate and synthesis of other substances including several neurotransmitters between brain CK double knock-out and wt animals with high temporal resolution. Transgenic mice are investigated which lack guanidinoacetate methyltransferase (GAMT) and, as a result, lack creatine. These animals serve as a faithful model for GAMT deficiency in humans, but were also expected to provide important information on the role of Cr/CK circuit, additional to the data obtained from CK deficient mice. The last chapter, deals with the visibility of Cr in human 1H MRS.
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