Duchenne muscular dystrophy (DMD) is a fatal, x-linked disease that causes progressive muscle weakness and susceptibility to damage. DMD is caused by a lack of dystrophin, a large muscle protein that performs both structural and signaling functions. A promising treatment currently in clinical trials is microdystrophin gene therapy, which delivers a truncated version of dystrophin to muscle via a viral vector. Preclinical studies have established efficacy of microdystrophin to improve muscle quality and function. With clinical success of this treatment, patients affected by DMD could become more physically active. However, the effect of exercise on both dystrophic and gene therapy-treated muscles is unclear. Recently, we demonstrated that microdystrophin gene therapy with and without 21 weeks of voluntary wheel running (VWR) improved treadmill time to fatigue and in vivo plantarflexor torque output in young mdx mice, a mouse model of DMD. Although treated mice could run well, diaphragm force and power output were blunted by VWR. A subsequent study tested longevity of two different microdystrophin gene therapy constructs in combination with VWR. Versions of each construct are being tested in clinical trials. Construct 1 contained the nNOS-binding site found in full-length dystrophin, which localizes nNOS to the sarcolemma and reduces functional ischemia of exercising limb muscles, while construct 2 lacked the nNOS-binding site and was the same microdystrophin used in the previous study. Gene- therapy treated mice that were sedentary or performed 52 weeks of VWR demonstrated similar outcomes including increased plantarflexor torque and exceptional treadmill endurance capacity. However, ex vivo diaphragm and soleus force, as well as metabolic enzyme and mitochondrial respiration assays were differentially improved, revealing unique physiological adaptations to each microdystrophin construct. Together, the data demonstrated that response to exercise after gene therapy treatment was variable and dependent on age, microdystrophin construct, and muscle type. / Doctor of Philosophy / Duchenne muscular dystrophy (DMD) is a rare, fatal muscle disease that causes progressive muscle weakness and cardiorespiratory failure. Available treatments, such as corticosteroids, slow progression of the disease but do not address the underlying genetic cause. DMD is caused by a genetic mutation that results in the loss of the muscle protein dystrophin. Microdystrophin gene therapy aims to address the genetic cause of the disease by using a non-pathogenic virus to deliver microdystrophin, a small, functional version of dystrophin, to muscle. This gene therapy is in clinical trials, and, if it is successful, treated patients will likely want to engage in more physical activity than previously possible due to muscle weakness. However, the effects of physical activity on muscles treated with gene therapy are unclear. Therefore, we conducted two studies to test the effects of voluntary wheel running on microdystrophin gene therapy in the mdx mouse, a model of DMD. The first study demonstrated that voluntary wheel running was beneficial to whole-body muscle function in mice treated with microdystrophin gene therapy. However, adaptations to the gene therapy and voluntary wheel running were variable in individual muscles. In the second study, we tested two microdystrophin constructs, which each contain different structural components of full-length dystrophin. In addition, mice ran for 52 weeks, more than twice as long as the first study. The results of the second study found that adaptations in individual muscles depended on microdystrophin construct and activity level. Additionally, we confirmed that voluntary wheel running was beneficial to whole-body function of microdystrophin–treated muscles. Together, these studies demonstrated that adaptations of gene therapy-treated muscles were dependent on microdystrophin structure, activity level, and age.

Aortic baroreflex (ABR) control of blood pressure was examined in 7 untrained (UT) and 8 endurance exercise trained (EET) young men. ABR control of blood pressure was determined during a steady state phenylephrine infusion to increase mean arterial pressure 10-15 mmHg, combined with positive neck pressure to counteract the increased carotid sinus transmural pressure, and low levels of lower body negative pressure to counteract the increased central venous pressure. Functioning alone, the ABR was functionally adequate to control blood pressure. However, ABR control of HR was significantly diminished in the EET subjects due solely to the decrease in the ABR sensitivity. The persistent strain from an increased stroke volume resulting from endurance exercise training could be the responsible mechanism.

Mixed results, in terms of performance benefits, have been found when comparing carbohydrate (CHO) and carbohydrate-protein (CHO-P) supplementation during endurance exercise. Thus this study assessed performance from three different supplements (CHO-P, CHO, double carbohydrate [CHO-CHO]) as compared to a placebo (PLA) during a time trial (TT) run. Twelve male recreational runners (age = 32.4 ± 9.5 yrs; body mass index [BMI] = 22.7 ± 1.5 kg/m2; VO2max = 59.68 ± 7.53 mL/kg body weight; 100% white) individually completed four, 12-mile TT runs, 7-10 days apart, at about 75% of the their race pace. Dietary and physical activity consistency within the 24-hour time period prior to each run was controlled via individualized diet and activity prescriptions based off of the diet consumed and the physical activity engaged in prior to TT 1. Throughout each TT run, participants consumed a 600 mL load of one of the four aforementioned supplements. Supplement order was counterbalanced with a latin-square design. Endurance performance was measured by time to complete the 12-mile run, and time to complete the last 1.2 miles of the run, where participants were instructed to run at maximal effort, 100% race pace. A main effect of time occurred during the TTs for perceived exertion (RPE) and heart rate (HR). RPE (Borge 10-point scale) significantly increased from the mid-point of the TT to completion of the run (4.7 ± 0.7, 9.7 ± 0.9, p < 0.001); HR significantly increased from the start of the run to the start of the maximal effort, and was significantly higher at completion of the effort (84.4 ± 14.5 bpm, 166.0 ± 8.3 bpm, 178.8 ± 7.4 bpm, p < 0.001). No significant difference was found in overall time to complete the 12-mile run or maximal effort between the supplements (PLA = 88.6 ± 11.6 min, CHO = 89.1 ± 11.3 min, CHO-P = 89.1 ± 11.8 min, CHO-CHO = 89.6 ± 11.9 min; PLA = 8.3 ± 1.2 min, CHO = 8.2 ± 1.2 min, CHO-P = 8.2 ± 1.2 min, CHO-CHO = 8.4 ± 1.5 min). These findings suggest that type of supplementation (CHO, CHO-CHO, CHO-P) consumed during an endurance exercise bout has no influence on enhancing endurance performance in male recreational runners during TT runs less than 100 minutes in length.

Orientador: Jaime Amaya-Farfan / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia de Alimentos / Made available in DSpace on 2018-08-15T06:19:51Z (GMT). No. of bitstreams: 1 Costa_GiovanaErmeticedeAlmeida_D.pdf: 896103 bytes, checksum: 9bd11829f054f3e4de67f748821a4ab4 (MD5) Previous issue date: 2010 / Resumo: A atividade física (AF) de resistência provoca diversas respostas fisiológicas, dentre elas a alteração dos padrões de células sangüíneas e atividade enzimática. Recursos alimentares são freqüentemente utilizados para aumentar o rendimento esportivo e minimizar os danos causados pelo exercício. O tipo de proteína e sua forma são determinantes dos efeitos que estas podem proporcionar. As proteínas do soro do leite (PSL) são fontes de aminoácidos indispensáveis, dentre eles, os de cadeia ramificada que estão envolvidos na sinalização da síntese protéica e no metabolismo energético, e os sulfurados que se destacam por serem precursores para a formação de glutationa. Este trabalho foi realizado com o objetivo de verificar os efeitos do consumo de dietas contendo proteínas do soro do leite, nas formas intacta e pré-hidrolisada, no desempenho, composição corporal e parâmetros bioquímicos e hematológicos de ratos submetidos à atividade física em esteira. Foram utilizados animais machos divididos em dois grupos de acordo com a prática (treinados) ou não (sedentários) de AF, sendo estes subdivididos em três grupos conforme o tipo de proteína (AIN-93M): caseína (controle), e PSL nas formas intactas ou pré-hidrolisadas como única fonte de proteínas, totalizando 6 grupos experimentais. Os ratos ativos correram cinco dias por semana, durante nove semanas consecutivas seguindo protocolo de treinamento com velocidade e tempo progressivos. O desempenho dos animais foi crescente ao longo do experimento em todos os grupos e a evolução de peso foi similar independentemente da dieta ou da prática de AF. Os resultados hematológicos e bioquímicos mostraram efeito redutor do treinamento sobre os parâmetros analisados sem interferência especifica da dieta, à exceção da concentração de glutationa total em eritrócitos que foi significativamente superior em animais sedentários que consumiram PSL intactas. A composição química da carcaça revelou um perfil lipídico reduzido em animais treinados em comparação aos sedentários, com significância estatística somente em relação aos grupos que receberam PSL, mostrando ser um efeito positivo e dependente da ação conjunta da dieta e da AF. Dados de peso dos órgãos apontam possível influência das PSL sobre o fígado e pâncreas, mas o peso e o comprimento dos fêmures não mostraram alteração nem pelo tipo de dieta nem pelo treinamento. Assim, concluiu-se que os resultados obtidos nesse estudo são, em sua maioria, decorrentes do efeito do treinamento, e que as PSL ao nível oferecido na dieta (12%), mesmo apresentando diferente forma físico-química, não causaram variações hematológicas e bioquímicas significativas quando avaliadas, respectivamente, após 24 horas da última sessão de treino e passadas 48 horas do teste de desempenho final. Ressalta-se, entretanto, o potencial antioxidante dessas proteínas pelo incremento da glutationa intracelular / Abstract: Endurance exercise leads to many physiological responses, as changes in the blood cells and enzymatic activity. Food resources are often used to improve the sport performance and diminish injuries caused by exercise. The type and form of protein are determinant of the effects that they can provide. Milk whey proteins (MWP) are sources of indispensable amino acids, among them the branched-chain amino acids are involved in protein synthesis signaling and energetic metabolism, and sulfur ones point out in order to be precursors for glutathione formation. This work was conducted with the objective of verifying the effects of consuming diets containing MWP, in intact or pre-hydrolyzed forms over performance, body composition, biochemical and hematological parameters in rats undergoing a treadmill exercise. Male animals, segregated into two groups according to the practice (trained) or not (sedentary) of exercise, were used. They were subsegregated into three groups regarding the type of protein in the diet (AIN-93M): casein (control), and intact or pre-hydrolyzed MWP as the only source of protein, for a total of 6 groups. Active rats run 5 d/wk, during nine consecutive weeks, following a progressive time and speed protocol. The performance of the animals increased for all groups along the experiment and weight evolution remained similar independent of the diet and exercise. Hematological and biochemical results showed that training had a diminishing effect over the analyzed parameters without specific interference of the diet, except for total glutathione concentration in erythrocytes that was significantly higher in the sedentary animals that consumed intact MWP. Carcass chemical composition revealed a decreased lipid profile in trained animals compared to sedentary, with statistical significance only related to the groups that received MWP showing a positive dependence from the combined action of diet and exercise. Analyses of organ weight data suggest a possible influence of MWP upon liver and pancreas, but weight and length of femurs did not show to be changed either by diet or exercise. Thus, it was concluded that outcomes obtained in this study are mostly due to training, and that MWP at the level offered in the diet (12%), even in different physical-chemical forms, did not cause significant hematological and biochemical variation when analyzed, respectively, 24 hours after the last training session and 48 hours from the final performance test. It should be noted, however, the antioxidant potential of these proteins by increased intracellular glutathione / Doutorado / Nutrição Experimental e Aplicada à Tecnologia de Alimentos / Doutor em Alimentos e Nutrição

Peak oxygen uptake (VO2PEAK) in endurance exercise trained (ET =8) subjects (VO2PEAK = 61.7 1.6 ml 02.kg.min-1) was compared to the V02 PEAK of untrained (UT = 8) subjects (V02 PEAK = 38.4 1.7 ml 02 -kg.min1) after four hours of -6* head-down rest (HDR).Although both groups showed a reduction in blood volume (BV) following HDR, this decrement was greater for ET subjects (delta BV = -3.23 0.46 mi/kg; P <0.05). The ET subjects had a greater decrease in VO2=(delta 02E -5.58 1.05 ml 02-kg.min-1; P <0.05) than their UT peers (VO2PEAK = -2.44 0.79 ml02-kg.min-1). These data suggest that the greater reductions in VO2PE, observed for the ET group were associated with a greater BV loss resulting from 4 h of HDR prior to exercise.

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第19042号 / 農博第2120号 / 新制||農||1032(附属図書館) / 学位論文||H27||N4924(農学部図書室) / 31993 / 京都大学大学院農学研究科食品生物科学専攻 / (主査)教授 伏木 亨, 教授 保川 清, 教授 金本 龍平 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

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Glucose is a fundamental energy source, the utilization and regulation of which impacts exercise performance and health. These studies have used modeling techniques to evaluate glucose kinetics and dynamics in equids and developed tests to evaluate the status of glucose metabolism. In Part I, 12 exercise-trained Arabians underwent insulin-modified FSIGT (with minimal model analysis) and single-injection glucose tracer (with compartmental analysis) studies at rest and during exercise to evaluate the effects of exercise on glucose kinetics and dynamics. These geldings were maintained on pasture, but adapted for 4 months to twice-daily feeding of feeds rich in sugar and starch (SS, n=6: NSC 45%, Fat 3%, NDF 24%) or fat and fiber (FF, n=6:NSC 13%, Fat 11%, NDF 45% ). Exercise increased insulin sensitivity (P = 0.070) and glucose transport (P < 0.038). Although variables were not different between FF and SS horses at rest, during exercise SS horses tended to have lower (P = 0.085) insulin sensitivity and increased (P = 0.043) glucose utilization compared to FF horses. In Part II, satisfactory proxies for minimal model parameters were developed to facilitate the evaluation of insulin sensitivity in larger populations. These proxies were applied to a population of 163 ponies and used to characterize metabolic differences between ponies predisposed to pasture laminitis (PL) from ponies not predisposed (NL). A subset of 14 ponies (7 PL, 7 NL) also underwent the FSIGT for minimal model analysis. Ponies predisposed to laminitis were found to have lower insulin sensitivity (P < 0.007) and higher insulin secretory response (P < 0.045) by both the minimal model and proxies, and higher (P < 0.001) circulating triglycerides and body condition score. Cut-point analysis for these variables was used to define a pre-laminitic metabolic syndrome with total predictive power of 78% to identifity ponies at risk for developing pasture laminitis. Increased insulin resistance and prevalence of lamintis were associated with increased non-structural carbohydrates in spring pasture. These studies demonstrate the importance of glucose regulation for exercise and animal health. When glucose regulation is altered in the case of insulin resistance, performance could be impacted and diseases such as laminitis may occur. Insulin resistance may be moderated by exercise or by avoiding sugar and starch in feeds and pasture. / Ph. D.

The strength model of self-control suggests that self-regulation and self-control processes are governed by finite internal energy resources. However, this perspective has recently come under scrutiny suggesting that self-control processes are not solely constrained to limited resources and may also be guided by motivational-cognitive processing. Self-efficacy theory and control theory are two theoretical views of self-regulation that also suggest self-regulation failures are dependent on motivational-cognitive processes; however the potential role of limited resources has not been evaluated in the context of these theoretical views. This dissertation sought to advance our understanding of self-regulation and self-control of exercise behaviour by integrating the three theoretical perspectives discussed above. Study 1 showed that self-control depletion leads to reductions in task self-efficacy mediating the self-control depletion – negative performance change relationship. Overall, findings are consistent with self-efficacy theory. However the results are limited as the mechanism(s) leading to reduced self-efficacy following self-control depletion remain unclear. Study 2 explored a sequential (serial) mediation model investigating the idea that exerting self-control leads to an altered psychophysiological state increasing subjective fatigue, which in turn, leads to reduced self-efficacy to exert self-control and reductions in physical self-control performance. Findings supported the proposed sequential mediation model. However, it remains unclear to what extent that self-efficacy plays a passive or active role guiding self-controlled behaviour following self-control depletion. Study 3 explored the independent and interactive effects of self-control depletion and normative performance feedback on self-efficacy and physical self-control. Findings showed an interaction between self-control depletion and feedback. Findings support predictions of control theory when self-control resources are intact, but suggest feedback information is processed differently when self-control strength is depleted. Overall, results show that when self-efficacy is manipulated by feedback the effects of self-control depletion on performance are no longer evident supporting self-efficacy’s role as an active causal mechanism determining behaviour. / Dissertation / Doctor of Philosophy (PhD) / Self-control failures are at the heart of many societal problems. A dominant theoretical view suggests self-control is governed by a limited internal resource. However, this perspective has recently been opposed by theorizing and evidence suggesting that people experience self-control failures due to shifts in motivational-cognitive processes. This thesis integrated three theories of self-control (i.e., strength model of self-control, control theory, and self-efficacy theory) in an attempt to provide a more complete understanding of why self-control failures occur for people performing demanding physical exercise. Findings suggest that each theoretical perspective provides complementary explanations for why self-control failures occur and how they can be overcome through shifts in cognitive processing. Specifically, self-control exertion leads to subjective fatigue, which decreases self-efficacy to exert self-control, and in turn reduces self-control performance. Furthermore, after self-control exertion, positive normative performance feedback increases self-efficacy and subsequent self-control performance whereas negative feedback drastically reduces self-efficacy and performance.

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