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Thesis (M.S.)--Florida State University, 2005. / Advisor: Dr. W. Ross Ellington, Florida State University, College of Arts and Sciences, Dept. of Biological Science. Title and description from dissertation home page (viewed June 15, 2005). Document formatted into pages; contains x, 51 pages. Includes bibliographical references.

Thesis (Ph. D.)--West Virginia University, 2003. / Title from document title page. Document formatted into pages; contains xii, 156 p. : ill. (some col.). Includes abstract. Includes bibliographical references.

Heart failure (HP) is a common, disabling and deadly condition that causes high rates of morbidity and mortality worldwide. It is widely recognised that the failing heart is energy-starved, and that restoring energy homeostasis is a promising approach towards improving cardiac output. This thesis aims to address the role of energetics in the failing heart, by focussing on modulation of the creatine transporter (CrT). Creatine (Cr), together with the phosphocreatine shuttle, plays a vital role in maintaining energy supplies via ATP in times of high energy demand. Key to the regulation of intracellular [Cr] is the CrT, a Na+ and Cl - dependent membrane transporter. Previous CrT genetic mouse models include a knockout model, found to still express cardiac CrT, and a cardiac-specific CrT overexpressing (OE) model with large variations in myocardial [Cr] between animals and Cr levels high enough to cause spontaneous hypertrophy. To overcome the shortfalls of this CrT-OE model, a novel in vivo model of temporal inducible expression of CrT is described, using a cardiac-specific tetracycline inducible (Tet-On) system . ..,. .A' Ten transgenic lines (RCT) were created with a construct containing . zhe CrT-HA (CrT cDNA with an haemagglutinin epitope tag), following successful doxycyline-inducibility in vitro. Eight lines showed germline transmission, with LV CrT OE achieved in an individual mouse that displayed double LV [Cr] compared to WT. Issues with the inducer line (rtTA) were ruled out by its use in the creation of a luciferase overexpressing mouse line; all mice tested demonstrated LV luciferase expression in response to doxycycline feeding. The failure to overexpress CrT could be attributed to position or copy number dependent suppression, or to position effect variegation in the case of the single OE mouse obtained. Subsequent work focus sed on regulatory pathways in vitro in a cell line of mouse fibroblasts stably overexpressing CrT·HA. Post-translational modifications (PTMs) had been previously suggested to regulate CrT activity. Two N-linked glycosylation sites exist, in addition to the putative phosphorylation sites. Inhibition of glycosylation by tunicamycin led to decreased CrT activity, reflected by decreased Cr uptake capacity. Strategies to confirm the presence of phosphorylation were employed, including isolation of CrT -HA by immunoprecipitation and subsequent LC-MS / MS analysis to identify PTMs. Although the presence of CrT was confirmed in 5 different sized species- one previously unreported- inadequate sequence coverage prevented identification of any PTM sites. Tyrosine phosphorylation was not detected using a phosphospecific antibody on immunopurified CrT -HA. Candidate signalling pathways in vitro were then investigated to elucidate CrT regulation, namely the IGF-IR signalling pathway. This study included a cardiomyocyte-like mouse cell line (HL-l) in addition to 3T3-CrT -HA. Exposure of cells to extracellular insulin, growth hormone and IGF-1 led to increased Cr uptake of 125% - 300% of normal. Pharmacological inhibition of the downstream kinases PKA and PKC reduced the effect of insulin and GH, while PMA, sapintoxin (STX) and Go 6976 induced CrT activity. The mammalian target of rapamycin (mTOR) is also a candidate regulator of CrT, as incubation with rapamycin decreased Cr uptake in 3T3-CrT -HA. Finally, a targeted approach on transcription factors in the 5'UTR region of mouse CrT identified HEYl as a highly conserved site. In siRNA experiments, HEYl was found to exert a mild effect on CrT activity, suggesting that regulation at the transcriptional level merits further investigation. Together, this work has provided novel insights into the modulation of CrT in vitro, identifying molecular and pharmacological targets in a known therapeutic signalling pathway. Further work could potentially develop these findings by identifying candidate compounds that would increase CrT activity, potentially in a tissue-specific manner. 3

The purpose of this thesis was to determine ways to maximize creatine uptake and retention during creatine supplementation. Since there are many factors that affect muscle creatine concentrations, a series of studies were performed. In the first study, the purpose was to determine if á-lipoic acid aided creatine uptake and retention. It was hypothesized that á-lipoic acid would increase creatine uptake, because it has been found to increase glucose disposal in animal studies and because creatine uptake has been found to be related to increased glucose transport. Results showed that phosphocreatine and total creatine increased following supplement intervention. In the second study, the purpose was to develop an optimal dose of creatine in order to minimize urinary excretion of creatine. It was hypothesized that individuals with more lean tissue mass would excrete less urinary creatine during consumption of the same loading dose. There was a high negative correlation between lean tissue mass and urine creatine excretion. Regression equations were developed for the relationship between lean tissue mass and urine total creatine and used to determine the amount of creatine to ingest relative to lean tissue mass that would result in minimal creatine losses in urine. Based on these results, a creatine dose of 0.22 [right arrow] 0.25 g/kg lean tissue mass/d was recommended. In the third study, the purpose was to determine if a habitual vegetarian diet resulted in lower muscle creatine and phosphocreatine concentrations compared to an omnivorous diet. A secondary purpose was to determine if creatine supplementation and weight training resulted in greater increases in muscle metabolite content, muscle fiber area, lean tissue mass, and strength in vegetarians compared to non-vegetarians. Results indicated that vegetarians had lower resting total creatine concentration, and that creatine supplementation and weight training led to greater increases in muscle phosphocreatine and total creatine in vegetarians compared to non-vegetarians (p < 0.0125). The supplement and exercise intervention eliminated the differences in intramuscular total creatine concentration that existed prior to the study. Type II muscle fiber area, lean tissue mass, total work output, and 1-RM bench press increased to a greater extent following creatine supplementation compared to placebo supplementation (p < 0.017), with no difference between vegetarians and non-vegetarians. (Abstract shortened by UMI.)

Thesis (M.S.)--Florida State University, 2005. / Advisor: Dr. Ross Ellington, Florida State University, College of Arts and Sciences, Dept. of Biological Science. Title and description from dissertation home page (viewed June 8, 2005). Document formatted into pages; contains xiii, 55 pages. Includes bibliographical references.

Thesis (M.S.)--University of North Carolina at Wilmington, 2006.

Children and adolescents are thought to use oxidative metabolism to a greater extent than adults during high intensity exercise. The studies reported in this thesis examine the nature and implications of age-related differences in muscle metabolism during high intensity exercise and recovery. Chapter 4 concluded that during heavy intensity exercise, phosphocreatine (PCr) kinetics did not differ with age or sex, while Chapter 5 revealed that during very heavy intensity exercise, the fundamental τ was slower and slow component amplitude greater in men compared with adolescent boys, indicating that exercise intensity might play a role in determining age-related differences in muscle metabolism. In Chapter 6, two bouts of very heavy intensity exercise were completed, and prior exercise reduced the PCr slow component amplitude in men but not boys. Deoxyhaemoglobin (HHb) kinetics was faster in adolescents compared with adults during both heavy and very heavy intensity exercise, indicating that matching of oxygen delivery to oxygen utilisation is less precise at the onset of exercise in adolescents compared with adults. PCr recovery from high intensity exercise was faster in boys than men, but not different in girls and women, as described in Chapter 7. The speed of PCr recovery was correlated with maturity in adolescents, but was not correlated with end-exercise [PCr] or pH. Two different tests to measure mitochondrial capacity in adolescents were evaluated in Chapter 8, and a fitted curve and gated test were both used to determine PCr recovery kinetics. Finally, in Chapter 9, age-related differences in muscle metabolism and oxygenation during fatiguing exercise were examined; a strong trend for greater fatigue in adults compared with adolescents was accompanied by greater metabolic perturbation in adults. Overall, these data show that muscle metabolism and oxygenation differs between adolescents and adults during and following very high intensity exercise.

Introdução: Postula-se que a creatina (ácido-metil-guanadino-acético), descrita como um \"tampão energético\" dos processos metabólicos cerebrais, poderia melhorar o desempenho cognitivo nos indivíduos em desenvolvimento. Objetivo: Investigar os efeitos da suplementação com creatina na função cognitiva e nas concentrações cerebrais em crianças saudáveis. Métodos: O presente ensaio-clínico, duplo-cego, randomizado e controlado por placebo, foi composto por 67 crianças saudáveis com idades entre 10 e 12 anos (11,5 ± 0,8). Os participantes receberam 0,3g/Kg/dia de creatina monohidratada (n= 35) ou dextrose (n=32). No período basal, e após sete dias de intervenção, os participantes foram submetidos à bateria de testes cognitivos. Em uma sub amostra aleatória de participantes (creatina: n = 11 e placebo: n = 10), as concentrações cerebrais de creatina foram avaliadas no córtex pré-frontal dorsolateral esquerdo, hipocampo esquerdo e lobo occipital, pela técnica de espectroscopia por ressonância magnética (1H-ERM). Resultados: Os escores obtidos nos testes de função executiva e aprendizagem verbal não foram estaticamente diferentes entre os grupos antes ou após a intervenção (p > 0,05). As concentrações cerebrais de creatina (expresso em mmol/L) não foram estaticamente diferentes entre os grupos no córtex pré-frontal dorsolateral esquerdo (creatina - pré: 6,9 ± 0,8, pós: 6,7 ± 0,5; placebo - pré: 6,7 ± 0,8; pós: 6,9 ± 0,09; p = 0,50), hipocampo esquerdo (creatina - pré: 7,0 ± 0,5, pós: 6,8 ± 0,7; placebo - pré: 6,7 ± 1,0; pós: 6,6 ± 1,9; p = 0,80), e no lobo occipital (creatina - pré: 7,9 ± 0,9, pós: 8,1 ± 0,8; placebo - pré: 7,7 ± 0,4; pós: 7,8 ± 0,5; p = 0,70). Conclusão: o protocolo de suplementação de creatina por sete dias mostrou-se incapaz de provocar aumento nas concentrações cerebrais de creatina ou no desempenho cognitivo em crianças. Esses dados sugerem que essa população depende principalmente da síntese cerebral do que a creatina exógena para manter a homeostase desse nutriente no cérebro / Background: It has been hypothesized that creatine (?-methyl-guanidine-acetic acid), which is thought to energetically buffer brain metabolic processes, could enhance cognitive performance in developing individuals. Aims: This study aimed to investigate the effects of creatine supplementation on cognitive function and brain creatine concentration in healthy youth. Methods: This was a 7-day, double-blind, randomized, placebo-controlled study. The sample comprised 67 healthy children aged 10 to 12 years. The participants were given either creatine supplementation ((0.3 g/Kg/day; n = 35) or 2) placebo (dextrose; n = 32). At baseline and after 7 days of intervention, participant undertook a battery of cognitive tests. In a random sub-sample of participants (creatine: n = 11 and placebo: n = 10), brain creatine concentration was also assessed in left dorsolateral prefrontal cortex, left hippocampus, and occipital lobe, by proton magnetic resonance spectroscopy (1H-MRS) technique. Results: As a result, scores obtained from Rey Auditory Learning Test, Stroop Test, Trail Making Test, and Raven Progressive Matrices did not significantly differ between groups at baseline or after the intervention (all p > 0.05). Creatine concentration (expressed in mmol/L) was not significantly different between groups in left dorsolateral prefrontal cortex (creatine - pre: 6.9 ± 0.8, post: 6.7 ± 0.5; placebo - pre: 6.7 ± 0.8; post: 6.9 ± 0.09; p = 0.50), left hippocampus (creatine - pre: 7.0 ± 0.5, post: 6.8 ± 0.7; placebo - pre: 6.7 ± 1.0; post: 6.6 ± 1.9; p = 0.80), and occipital lobe (creatine - pre: 7.9 ± 0.9, post: 8.1 ± 0.8; placebo - pre: 7.7 ± 0.4; post: 7.8 ± 0.5; p = 0.70). Conclusion: In conclusion, a 7-day creatine supplementation protocol did not elicit improvements in brain creatine concentration or cognitive performance in healthy youth, suggesting that this population mainly rely in brain creatine synthesis rather than exogenous creatine intake to maintain brain creatine homeostasis