Matching Items (9)
Description
Cardiovascular disease and diabetes are major health burdens. Diabetes is a primary risk factor of cardiovascular disease, and there is a strong link between obesity and risk of developing diabetes. With the prevalence of prediabetes highest among overweight/obese individuals, investigation into preventative strategies are needed. Aerobic exercise is a potent stimulus for both insulin and non-insulin dependent glucose uptake into the skeletal muscle. A single exercise session can improve insulin sensitivity within hours after exercise. The effects of intensity, type, and volume of exercise on glucose homeostasis have been studied extensively; however, controlling for muscle contraction frequency with a constant exercise intensity and workload has not been examined. The purpose of this study was to compare muscle contraction frequency during aerobic exercise by altering cycling cadence on insulin sensitivity and vascular health. Eleven obese males (age=28yr, BMI=35kg/m2) completed three conditions in random order: 1) control-no exercise; 2) 45-min cycling at 45 revolutions per minute (45RPM) at 65-75%VO2max; 3) 45-min cycling at 90RPM at 65-75%VO2max. Glucose control and insulin sensitivity were assessed with oral glucose tolerance tests (OGTT) 4 hours post-exercise. Vascular health was assessed via flow-mediated dilation (FMD) pre-exercise, 1-hr and 2-hr post exercise and ambulatory blood pressure was assessed pre-exercise, and continually every 15 min post-exercise. Linear mixed models were used to compare the mean differences in outcome variables. There were no significant differences found between control and both exercise conditions for all OGTT outcomes and no differences were found between control and exercise in FMD (all, p>0.05). Significant effects for exercise were found for both brachial and central blood pressure measures. Brachial systolic blood pressures were lower at 2- and 4-hr post-exercise by approximately -10 and -8mmHg, respectively (p<0.001 and p=0.004) versus control. Central systolic blood pressures were lower at 2-, 3-, and 4-hr post-exercise by approximately -8, -9 and -6mmHg, respectively (p<0.001, p=0.021 and p=0.004) versus control. In conclusion, aerobic exercise, regardless of muscle contraction frequency, were unable to effect glucose control and insulin sensitivity. Similarly, there was no effect on vascular function. However, there was a significant effect of aerobic exercise on reducing post-exercise blood pressure.
ContributorsJarrett, Catherine Lee (Author) / Gaesser, Glenn A (Thesis advisor) / Angadi, Siddhartha S (Committee member) / Dickinson, Jared M (Committee member) / Whisner, Corrie M (Committee member) / Todd, Michael W (Committee member) / Arizona State University (Publisher)
Created2017
Description
The purpose of this dissertation was 1) to develop noninvasive strategies to assess skeletal muscle size, architecture, and composition in young and old adults (study #1) and 2) evaluate the impact of chemotherapeutic treatment on skeletal muscle satellite cells and capillaries (study #2). For study #1 ultrasound images were obtained from the quadriceps muscles of young (8 m, 8 f) and older (7 m, 5 f) participants on two occasions, separated by 5-15 days. Images were collected while the participants were both standing and supine, and were analyzed for muscle thickness, pennation angle, and echogenicity. In addition, test-retest reliability and ICCs were evaluated for each posture and when imaging sites remained marked or were re-measured from visit #1 to visit #2. Generally, in both younger and older adults muscle thickness was greater and echogenicity was lower in the anterior quadriceps when images were collected standing versus supine. Maintaining the imaging site between visits did not influence test re-test reliability for either age group. Older adults exhibited smaller muscle thickness, lower pennation angle and increased echogenicity. Further, variability for the use of ultrasound to determine muscle thickness and pennation angle was greater in older versus younger adults. Findings from study #1 highlight several methodological considerations for US-based assessment of skeletal muscle characteristics that should be considered for improving reproducibility and generalizability of US to assess skeletal muscle characteristics and function across the aging spectrum. This is particularly relevant given the emerging use of ultrasound to assess skeletal muscle characteristics in healthy and clinical populations. In the second study, ovariectomized female Sprague-Dawley rats were randomized to receive three bi-weekly intraperitoneal injections of the chemotherapeutic drug, Doxorubicin (DOX) (4mg/kg; cumulative dose 12mg/kg) or vehicle (VEH; saline). Animals were euthanized 5d following the last injection, and the soleus (SOL) and extensor digitorum longus (EDL) muscles were dissected and prepared for immunohistochemical and RT-qPCR analyses. Relative to VEH, cross-sectional area (CSA) of the SOL and EDL muscle fibers were 26% and 33% smaller, respectively, in DOX animals (P<0.05). In the SOL satellite cell and capillary densities were 39% and 35% lower, respectively, in DOX animals (P<0.05), whereas in the EDL satellite cell and capillary densities were unaffected by DOX administration (P>0.05). In the SOL MYF5 mRNA expression was increased in DOX animals (P<0.05), while in the EDL MGF mRNA expression was reduced in DOX animals (P<0.05). Chronic DOX administration is associated with reduced fiber size in multiple skeletal muscles, however DOX appears to impact the satellite cell and capillary densities in a muscle-specific manner. These findings from study #2 highlight that therapeutic targets to protect skeletal muscle from DOX may vary across muscles. Collectively, these findings 1) improve the ability to examine muscle size and function in younger and older adults, and 2) identify promising therapeutic targets to protect skeletal muscle from the harmful effects of chemotherapy treatment.
ContributorsD'Lugos, Andrew (Author) / Dickinson, Jared M (Thesis advisor) / Buman, Matthew P (Committee member) / Gaesser, Glenn A (Committee member) / Huentelman, Matthew J (Committee member) / Katsanos, Christos S (Committee member) / Arizona State University (Publisher)
Created2018
Description
Parkinson’s disease (PD) is a progressive neurodegenerative disorder, diagnosed late in
the disease by a series of motor deficits that manifest over years or decades. It is characterized by degeneration of mid-brain dopaminergic neurons with a high prevalence of dementia associated with the spread of pathology to cortical regions. Patients exhibiting symptoms have already undergone significant neuronal loss without chance for recovery. Analysis of disease specific changes in gene expression directly from human patients can uncover invaluable clues about a still unknown etiology, the potential of which grows exponentially as additional gene regulatory measures are questioned. Epigenetic mechanisms are emerging as important components of neurodegeneration, including PD; the extent to which methylation changes correlate with disease progression has not yet been reported. This collection of work aims to define multiple layers of PD that will work toward developing biomarkers that not only could improve diagnostic accuracy, but also push the boundaries of the disease detection timeline. I examined changes in gene expression, alternative splicing of those gene products, and the regulatory mechanism of DNA methylation in the Parkinson’s disease system, as well as the pathologically related Alzheimer’s disease (AD). I first used RNA sequencing (RNAseq) to evaluate differential gene expression and alternative splicing in the posterior cingulate cortex of patients with PD and PD with dementia (PDD). Next, I performed a longitudinal genome-wide methylation study surveying ~850K CpG methylation sites in whole blood from 189 PD patients and 191 control individuals obtained at both a baseline and at a follow-up visit after 2 years. I also considered how symptom management medications could affect the regulatory mechanism of DNA methylation. In the last chapter of this work, I intersected RNAseq and DNA methylation array datasets from whole blood patient samples for integrated differential analyses of both PD and AD. Changes in gene expression and DNA methylation reveal clear patterns of pathway dysregulation that can be seen across brain and blood, from one study to the next. I present a thorough survey of molecular changes occurring within the idiopathic Parkinson’s disease patient and propose candidate targets for potential molecular biomarkers.
the disease by a series of motor deficits that manifest over years or decades. It is characterized by degeneration of mid-brain dopaminergic neurons with a high prevalence of dementia associated with the spread of pathology to cortical regions. Patients exhibiting symptoms have already undergone significant neuronal loss without chance for recovery. Analysis of disease specific changes in gene expression directly from human patients can uncover invaluable clues about a still unknown etiology, the potential of which grows exponentially as additional gene regulatory measures are questioned. Epigenetic mechanisms are emerging as important components of neurodegeneration, including PD; the extent to which methylation changes correlate with disease progression has not yet been reported. This collection of work aims to define multiple layers of PD that will work toward developing biomarkers that not only could improve diagnostic accuracy, but also push the boundaries of the disease detection timeline. I examined changes in gene expression, alternative splicing of those gene products, and the regulatory mechanism of DNA methylation in the Parkinson’s disease system, as well as the pathologically related Alzheimer’s disease (AD). I first used RNA sequencing (RNAseq) to evaluate differential gene expression and alternative splicing in the posterior cingulate cortex of patients with PD and PD with dementia (PDD). Next, I performed a longitudinal genome-wide methylation study surveying ~850K CpG methylation sites in whole blood from 189 PD patients and 191 control individuals obtained at both a baseline and at a follow-up visit after 2 years. I also considered how symptom management medications could affect the regulatory mechanism of DNA methylation. In the last chapter of this work, I intersected RNAseq and DNA methylation array datasets from whole blood patient samples for integrated differential analyses of both PD and AD. Changes in gene expression and DNA methylation reveal clear patterns of pathway dysregulation that can be seen across brain and blood, from one study to the next. I present a thorough survey of molecular changes occurring within the idiopathic Parkinson’s disease patient and propose candidate targets for potential molecular biomarkers.
ContributorsHenderson, Adrienne Rose (Author) / Huentelman, Matthew J (Thesis advisor) / Newbern, Jason (Thesis advisor) / Dunckley, Travis L (Committee member) / Jensen, Kendall (Committee member) / Wilson, Melissa (Committee member) / Arizona State University (Publisher)
Created2019
Description
Glyphosate is the most heavily used herbicide worldwide and recent reports indicate that it may have deleterious neurological and neurodegenerative effects on human health. Here I demonstrate that glyphosate can infiltrate the brain in a dose-dependent manner in mice sub-acutely exposed to 125, 250, or 500 mg/kg/day. I also establish that glyphosate elicits a neuroinflammatory response in both the cortex and hippocampus, marked by elevation of tumor necrosis factor α (TNFα), and causes transcriptomic dysregulation of key genes involved in oligodendrocyte proliferation, maturation, and myelination. Given that both the hippocampus and the cortex are critical for learning and memory, and are affected in Alzheimer’s disease (AD), I investigate how 50 or 500 mg/kg chronic glyphosate exposure influences locomotion, anxiety-like behavior, and cognition in the APP/PS1 mouse model of AD. Results show that while glyphosate did not influence weight, appearance, locomotion, or anxiety-like behavior, learning acquisition is impaired in the place preference and reaction time tasks following 500mg/kg chronic exposure. Additionally, I report a strong increase in water consumption in glyphosate-exposed mice, demonstrating that chronic glyphosate exposure induces polydipsia. To ascertain whether glyphosate influences AD pathogenesis, I examine neuropathological changes following chronic daily oral exposure to 50 or 500 mg/kg glyphosate. Post-mortem analysis of amyloid-beta (Aβ) in APP/PS1 hippocampal and cortical tissue show that 50 or 500 mg/kg of glyphosate elevates soluble and insoluble Aβ1-40 and Aβ1-42 in both sexes, with females showing higher levels. Further analysis of cortical TNFα levels in chronically exposed APP/PS1 mice and littermate controls confirms a neuroinflammatory response. I report no differences in amyloid precursor protein (APP) processing pathway components, CA1 NeuN+ neuronal number, relative density of Iba1+ microglia in the hippocampus, or relative density of MBP+ oligodendrocytes in the fimbria. I also show that 50mg/kg chronic glyphosate exposure elevates hemoglobin A1c levels, indicating disruptions in glucose metabolism that may be tied to polydipsia. Collectively, these results indicate that glyphosate crosses the blood-brain barrier, induces a neuroinflammatory response, and exacerbates amyloid pathology. Ultimately, these findings provide important insight into the concerns surrounding the neurological implications of glyphosate exposure.
ContributorsWinstone, Joanna (Author) / Velazquez, Ramon (Thesis advisor) / Newbern, Jason M (Committee member) / Huentelman, Matthew J (Committee member) / Leung, Maxwell (Committee member) / Coleman, Paul D (Committee member) / Arizona State University (Publisher)
Created2023
Description
Exercise serves as a powerful stimulus to induce skeletal muscle adaptation. For instance, it is well understood that aerobic exercise (AE) elicits an adaptive response ultimately leading to increased fatigue resistance and capillarization, whereas resistance exercise (RE) is known to elicit an adaptive response leading to increased muscle strength and size. However, the precise molecular mechanisms mediating these unique adaptations to different forms of exercise remain to be completely resolved. The purpose of this study was to investigate the adaptive cellular response of skeletal muscle following acute AE and RE. Specifically, this study focused on two molecular processes: 1) mammalian/mechanistic target of rapamycin (mTOR) signaling pathway, a regulator of muscle protein synthesis, and 2) autophagy, a process through which proteins and organelles are broken down in the muscle fiber. In a counterbalanced, crossover design, six healthy, recreationally active young men (27±3 yr) completed acute AE (40 min of cycling ~70% maximal HR) and acute RE [8 sets, 10 reps, ~65% 1-repetition maximum (1RM)] separated by ~1wk. Muscle biopsies (vastus lateralis) were obtained before, at 1 and 4h post exercise and western blot analyses were used to examine the phosphorylation of mTOR signaling proteins and various markers of autophagy. Phosphorylation of mTORSer2448 increased only following RE at 4h (P < 0.05). However, phosphorylation of p70S6K1Thr389, a downstream marker of mTOR, increased following both AE and RE at 4h (P < 0.05). However, p70S6K1Thr389 was phosphorylated to a greater extent at 1h following RE compared to AE (P < 0.05). LC3BII was decreased at 1h and 4h postexercise in response to both AE and RE (P < 0.05). These data indicate that both acute AE and RE stimulate, to some degree, mTOR signaling in skeletal muscle, a pathway associated with increased muscle protein synthesis. Further, based on markers examined in the current study, both acute AE and RE similarly stimulate autophagy, which is associated with muscle protein breakdown. These data indicate that, at least in the immediate hours post exercise, the unique adaptations to AE and RE exercise may be mediated through cellular pathways other than mTOR and autophagy.
ContributorsMazo, Corey (Author) / Dickinson, Jared M (Thesis advisor) / Carroll, Chad C (Committee member) / Angadi, Siddartha S (Committee member) / Arizona State University (Publisher)
Created2019
Description
Rapid advancements in genomic technologies have increased our understanding of rare human disease. Generation of multiple types of biological data including genetic variation from genome or exome, expression from transcriptome, methylation patterns from epigenome, protein complexity from proteome and metabolite information from metabolome is feasible. "Omics" tools provide comprehensive view into biological mechanisms that impact disease trait and risk. In spite of available data types and ability to collect them simultaneously from patients, researchers still rely on their independent analysis. Combining information from multiple biological data can reduce missing information, increase confidence in single data findings, and provide a more complete view of genotype-phenotype correlations. Although rare disease genetics has been greatly improved by exome sequencing, a substantial portion of clinical patients remain undiagnosed. Multiple frameworks for integrative analysis of genomic and transcriptomic data are presented with focus on identifying functional genetic variations in patients with undiagnosed, rare childhood conditions. Direct quantitation of X inactivation ratio was developed from genomic and transcriptomic data using allele specific expression and segregation analysis to determine magnitude and inheritance mode of X inactivation. This approach was applied in two families revealing non-random X inactivation in female patients. Expression based analysis of X inactivation showed high correlation with standard clinical assay. These findings improved understanding of molecular mechanisms underlying X-linked disorders. In addition multivariate outlier analysis of gene and exon level data from RNA-seq using Mahalanobis distance, and its integration of distance scores with genomic data found genotype-phenotype correlations in variant prioritization process in 25 families. Mahalanobis distance scores revealed variants with large transcriptional impact in patients. In this dataset, frameshift variants were more likely result in outlier expression signatures than other types of functional variants. Integration of outlier estimates with genetic variants corroborated previously identified, presumed causal variants and highlighted new candidate in previously un-diagnosed case. Integrative genomic approaches in easily attainable tissue will facilitate the search for biomarkers that impact disease trait, uncover pharmacogenomics targets, provide novel insight into molecular underpinnings of un-characterized conditions, and help improve analytical approaches that use large datasets.
ContributorsSzelinger, Szabolcs (Author) / Craig, David W. (Thesis advisor) / Kusumi, Kenro (Thesis advisor) / Narayan, Vinodh (Committee member) / Rosenberg, Michael S. (Committee member) / Huentelman, Matthew J (Committee member) / Arizona State University (Publisher)
Created2015
Description
Obesity is one of the most challenging health conditions of our time, characterized by complex interactions between behavioral, environmental, and genetic factors. These interactions lead to a distinctive obese phenotype. Twenty years ago, the gut microbiota (GM) was postulated as a significant factor contributing to the obese phenotype and associated metabolic disturbances. Exercise had shown to improve and revert the metabolic abnormalities in obese individuals. Also, genistein has a suggested potential anti-obesogenic effect. Studying the dynamic interaction of the GM with relevant organs in metabolic homeostasis is crucial for the design of new long-term therapies to treat obesity. The purpose of this experimental study is to examine exercise (Exe), genistein (Gen), and their combined intervention (Exe + Gen) effects on GM composition and musculoskeletal mitochondrial oxidative function in diet-induced obese mice. Also, this study aims to explore the association between gut microbial diversity and mitochondrial oxidative capacity. 132 adult male (n=63) and female (n= 69) C57BL/6 mice were randomized to one of five interventions for twelve weeks: control (n= 27), high fat diet (HFD; n=26), HFD + Exe (n=28), HFD + Gen (n=27), or HFD + Exe + Gen (n=24). All HFD drinking water was supplemented with 42g sugar/L. Fecal pellets were collected, DNA extracted, and measured the microbial composition by sequencing the V4 of the 16S rRNA gene with Illumina. The mitochondrial oxidative capacity was assessed by measuring the enzymatic kinetic activity of the citrate synthase (CS) of forty-nine mice. This study found that Exe groups had a significantly higher bacterial richness compared to HFD + Gen or HFD group. Exe + Gen showed the synergistic effect to drive the GM towards the control group´s GM composition as we found Ruminococcus significantly more abundant in the HFD + Exe + Gen than the rest of the HFD groups. The study did not find preventive capacity in either of the interventions on the CS activity. Therefore, further research is needed to confirm the synergistic effect of Exe, Exe, and Gen on the gut bacterial richness and the capacity to prevent HFD-induced deleterious effect on GM and mitochondrial oxidative capacity.
ContributorsOrtega Santos, Carmen Patricia (Author) / Whisner, Corrie M (Thesis advisor) / Dickinson, Jared M (Committee member) / Katsanos, Christos (Committee member) / Gu, Haiwei (Committee member) / Liu, Li (Committee member) / Al-Nakkash, Layla (Committee member) / Arizona State University (Publisher)
Created2021
Description
Maximal oxygen uptake (VO2max) declines with age and is a predictor of morbidity and mortality risks. Due to these implications, accurate assessment and determination of VO2max are important for the older population. Without the presence of a VO2 plateau, secondary criteria are used to determine whether the test resulted in a maximal value. However, inconsistent secondary criteria do not account for intersubject variability. To circumvent this issue, a verification phase following a traditional ramp assessment may be utilized. The purpose of this study was to compare verification phase strategies in older adults. A secondary purpose of this study was to examine the repeatability of the ramp assessment performed during each visit. Twenty-two older adults between 60 and 80 years of age were recruited to participate in the study. Each subject completed two experimental trials in a randomized, counterbalanced cross-over design. Both trials consisted of a ramp test and verification phase at either 85% (VP85) or 110% (VP110) of the peak work rate achieved during the ramp (Ramp85 and Ramp110, respectively). Expired gases and heart rate (HR) were monitored continuously and measured every ten seconds. VO2peak was determined by the highest 30-second averages for the ramp and verification phases. No significant differences were observed for absolute (L/min) VO2peak between VP85 (P = 0.679) or VP110 (P = 0.200) and the associated ramp. There was also no significant difference in maximal HR between VP85 (P = 0.243) or VP110 (P = 0.085) and the associated ramp. However, individual data shows that 36% of individuals achieved a 2% greater VO2 (L/min) during the VP85 compared to the Ramp85, while only 15% of subjects achieved a 2% greater VO2 (L/min) during the VP110 compared to Ramp110. No significant differences (P < 0.05) were found for most variables between Ramp1 and Ramp2. These data suggest that if a verification phase is employed for VO2max assessment in otherwise healthy older adults, a power slightly below peak work rate may provide a more accurate assessment compared to a power slightly above peak work rate.
ContributorsVillanueva, Ian Robert (Author) / Dickinson, Jared M (Thesis advisor) / Gaesser, Glenn A (Committee member) / Angadi, Siddhartha S (Committee member) / Arizona State University (Publisher)
Created2019
Description
PURPOSE: The aim of this study was to determine if the linear and nonlinear components of the energy expenditure-walking speed relationship are influenced by body mass index (BMI; kg/m2). The secondary aims were to determine if the relationship was influenced by age, height, and sex. METHODS: Subjects (n=182) walked at 2, 3, and 4 mph for six minutes each with oxygen consumption (V̇O2; ml/kg/min) and measured via indirect calorimetry and converted to energy expenditure (EE; W/kg). Because of the curvilinear change in metabolic rate with increase in walking speed, polynomial random coefficient regression (PRCR) was employed to produce a model which captures the slope of change. Individual level linear and quadratic coefficients were analyzed for relationships with BMI, age, height, and sex. RESULTS: The net V̇O2 regression formula for walking was 1.79(x-3)2+4.97(x-3)+9.32 where x is speed in mph. BMI was modestly correlated with the quadratic coefficients (r = 0.15 to 0.17, p = 0.02 to 0.04) but not the linear coefficients (r =0.02- 0.07, p = 0.36-0.78) for V̇O2 and EE. There was no difference in coefficients between normal BMI (18.5-<25.0 kg/m2), overweight (25-<30.0 kg/m2) and obese (>30.0 kg/m2) groups (H = 1.5-4.0, p = 0.13-0.48). Delta V̇O2 for 2-3 mph, 3-4 mph, and 2-4 mph were not correlated with BMI (r = -0.02 - 0.13, p = 0.11 - 0.41). Height was inversely correlated with the linear and quadratic coefficients (r = -0.32 to -0.14, p = 0.09). Age was not correlated to coefficients (r = -0.16 to 0.32, p = 0.06-0.44). The coefficients for sex were not different after controlling for height in ANCOVA (F(1,179)=0.3-2.9, p >0.09). Age was not correlated to coefficients (r = -0.16 to –0.32, p = 0.06-0.44). CONCLUSION: Although BMI had a modest relationship with the quadratic coefficient, it explained less than 3% of the variance in V̇O2 or EE. Combined with the absence of a delta V̇O2 or a linear component, BMI does not influence the energy expenditure-walking speed relationship. Height explained up to 9% of the variance in the coefficients and eliminated apparent sex differences. Age was not related to the coefficients.
ContributorsBeaumont, Joshua S (Author) / Gaesser, Glenn A (Thesis advisor) / Angadi, Siddhartha S (Thesis advisor) / Adams, Marc A (Committee member) / Dickinson, Jared M (Committee member) / Peterson, Daniel S (Committee member) / Arizona State University (Publisher)
Created2023