Kinesiology
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Item The Impact of Acute Aerobic Exercise on Semantic Memory Activation in Healthy Older Adults(2018) Won, Junyeon; Smith, Jerome C; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Background: A growing body of exercise literature use functional magnetic resonance imaging (fMRI) technique to measure the effects of exercise on the brain. Findings suggest that regular participation of long-term exercise is associated with enhanced cognitive function. However, fundamental questions regarding the beneficial effects of acute exercise on semantic memory have been ignored. Purpose: This study investigated the effects of a single session of exercise on brain activation during recognition of Famous names and Non-Famous names compared to seated-rest in healthy older adults (age 65-85) using fMRI. We also aimed to measure whether there are differences in brain activation during retrieval of Famous names from three distinct time epochs (Remote, Enduring, and Recent) following acute exercise. Methods: Using a within-subjects counterbalanced design, 30 participants (ages 55-85) will undergo two experimental visits on separate days. During each visit, participants will engage in 30-minutes of rest or stationary cycling exercise immediately followed by the famous name discrimination task (FNT). Neuroimaging and behavioral data will be processed using AFNI (version 17.1.06) and SPSS (version 23), respectively. Results: HR and RPE were significantly higher during exercise. Acute exercise was associated with significantly greater semantic memory activation (Famous > Non-Famous) in five out of nine regions (p-value ranged 0.027 to 0.046). In an exploratory epoch analysis, five out of 14 brain regions activated ruing the semantic memory task showed significantly greater activation intensity following the exercise intervention (Enduringly Famous > Non-Famous). Conclusions: Enhanced semantic memory processing is observed following acute exercise, characterized by greater fMRI response to Famous than Non-Famous names. Enduringly Famous names exhibited significantly greater activation after exercise compared to Non-Famous names. These findings suggest that exercise may improve semantic memory retrieval in healthy older adults, and may lead to enhancement of cognitive function.Item BIOLOGICAL AND FUNCTIONAL CHANGES IN SUPRASPINATUS MUSCLE AFTER ROTATOR CUFF TEAR(2017) Valencia, Ana Patricia; Spangenburg, Espen E; Hagberg, James M; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Rotator cuff (RTC) tears impair upper limb mobility and affect 20% of the adult population. Unfortunately, surgical repair of major RTC tears often fails to restore shoulder function and has a high risk of re-tear. RTC tears induce irreversible, degenerative changes to the muscle that may hinder the recovery of shoulder function. Currently, very few studies have comprehensively assessed RTC muscle function, thus, little is known about which markers may be able predict changes in function after RTC tear. In this dissertation, I present three studies designed to systemically determine the impact of a RTC tear on contractile function of the supraspinatus (SS), the muscle most commonly affected in the RTC. In study #1 I developed a novel method to test in vivo SS contractile function using animal species common to RTC research. In study #2, I found that the SS exhibited a 30% loss in force prior to onset of muscle atrophy after acute RTC tear using the rat model. The initial loss of force was associated with a decrease in the size and continuity of the neuromuscular junction (NMJ). The SS muscle was also more susceptible to injury, which was associated with a reduction in collagen packing density. Therefore, SS size is not the strongest predictor of force output with acute RTC tears. In addition, the increased susceptibility to injury could compound the dysfunction already apparent in the SS muscle after RTC tear. In study #3, I found that the rabbit model experienced a 40% loss of force after 6 weeks of RTC tear that persisted at 12 weeks. Using a number of different in vivo and ex vivo imaging approaches I found the degree of fatty infiltration (FI) to be the strongest predictor of muscle force production after RTC tear. Surprisingly, the data suggested that muscle atrophy only explained the loss in force in torn muscles when little to no FI was present. Therefore, FI is a prognostic marker for muscle weakness after RTC tear, and can help clinicians predict the force generating capacity of the SS for surgery and rehabilitation decision-making. Results from both studies found that SS contractile function was significantly impaired after RTC tear, and identified measureable markers beyond muscle atrophy that were associated with the loss in muscle force that may act as potential therapeutic targets to improve functional outcomes after RTC tear.Item The role of intracellular calcium perturbations in muscle damage and dysfunction in mouse models of muscular dystrophy(2016) Mázala, Davi Augusto Garcia; Chin, Eva R; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Duchenne muscular dystrophy (DMD) is a neuromuscular disease caused by mutations in the dystrophin gene. DMD is clinically characterized by severe, progressive and irreversible loss of muscle function, in which most patients lose the ability to walk by their early teens and die by their early 20’s. Impaired intracellular calcium (Ca2+) regulation and activation of cell degradation pathways have been proposed as key contributors to DMD disease progression. This dissertation research consists of three studies investigating the role of intracellular Ca2+ in skeletal muscle dysfunction in different mouse models of DMD. Study one evaluated the role of Ca2+-activated enzymes (proteases) that activate protein degradation in excitation-contraction (E-C) coupling failure following repeated contractions in mdx and dystrophin-utrophin null (mdx/utr-/-) mice. Single muscle fibers from mdx/utr-/- mice had greater E-C coupling failure following repeated contractions compared to fibers from mdx mice. Moreover, protease inhibition during these contractions was sufficient to attenuate E-C coupling failure in muscle fibers from both mdx and mdx/utr-/- mice. Study two evaluated the effects of overexpressing the Ca2+ buffering protein sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 1 (SERCA1) in skeletal muscles from mdx and mdx/utr-/- mice. Overall, SERCA1 overexpression decreased muscle damage and protected the muscle from contraction-induced injury in mdx and mdx/utr-/- mice. In study three, the cellular mechanisms underlying the beneficial effects of SERCA1 overexpression in mdx and mdx/utr-/- mice were investigated. SERCA1 overexpression attenuated calpain activation in mdx muscle only, while partially attenuating the degradation of the calpain target desmin in mdx/utr-/- mice. Additionally, SERCA1 overexpression decreased the SERCA-inhibitory protein sarcolipin in mdx muscle but did not alter levels of Ca2+ regulatory proteins (parvalbumin and calsequestrin) in either dystrophic model. Lastly, SERCA1 overexpression blunted the increase in endoplasmic reticulum stress markers Grp78/BiP in mdx mice and C/EBP homologous protein (CHOP) in mdx and mdx/utr-/- mice. Overall, findings from the studies presented in this dissertation provide new insight into the role of Ca2+ in muscle dysfunction and damage in different dystrophic mouse models. Further, these findings support the overall strategy for improving intracellular Ca2+ control for the development of novel therapies for DMD.Item Exercise training-associated differences in circulating microRNAs and serum-induced endothelial cell migration rate(2015) Sapp, Ryan M.; Hagberg, James M; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Cardiovascular Diseases (CVDs) are the primary source of global mortality and morbidity. The initial steps of CVD development occur in the endothelium. MicroRNAs (miRNAs) have recently emerged as novel regulators of cardiovascular physiology and pathology. Interestingly, regular aerobic exercise acts to prevent CVDs and also regulates miRNAs in the circulation (ci-miRNAs). The purpose of this study was to determine the effects of serum from highly active and sedentary, young, healthy individuals on migration rate of endothelial cells in vitro. Secondarily, CVD-associated ci-miRNAs in serum were compared between groups. The results of this study represent a novel way by which sedentary behavior may act as an early risk for CVD development before the appearance of other classic risk factors. RT-qPCR array analysis identified nine ci-miRNAs as > 4-fold differentially expressed in serum of trained versus inactive subjects, though more subjects are needed before any conclusions about ci-miRNA differences can be made.Item The role of ER stress in skeletal muscle atrophy in amyotrophic lateral sclerosis(2015) Chen, Dapeng; Chin, Eva R; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Amyotrophic lateral sclerosis (ALS) is a devastating disease which affects both motor neurons and skeletal muscle. Skeletal muscle atrophy and weakness are two of the main features of ALS disease progression. We hypothesized that disruptions in the sarcoplasmic reticulum and endoplasmic reticulum (SR/ER) play an important role in skeletal muscle pathology in ALS. This dissertation is comprised of three studies investigating ER stress in skeletal muscle and its relationship to oxidative stress and SR Ca2+ regulation. Study#1 established that the ER stress markers PERK, IRE1α and Grp78/BiP as well as the ER-stress specific apoptotic marker CHOP are upregulated in skeletal muscle of ALS transgenic (ALS-Tg) mice and that these changes were greater in fast white vs. slow red muscles. Study #2 showed that skeletal muscle-specific overexpression of the SR Ca2+ ATPase SERCA1 improved motor function, delayed disease onset and attenuated the muscle atrophy in ALS-Tg mice but did not attenuate the ER stress markers. Study #3 investigated the potential molecular mechanisms of ER stress in skeletal muscle pathology in ALS. This final dissertation study showed that the Grp78/BiP protein interacts with SERCA1 and various mitochondrial proteins including ATP synthase subunits in skeletal muscle of ALS-Tg but not wild-type mice. Disruption of the Grp78/BiP-SERCA1 protein-protein interaction by antibody sequestration of Grp78/BiP decreased SERCA ATPase activity, suggesting that Grp78/BiP preserves SERCA function. In C2C12 myocytes, oxidative stress induced by H2O2 dramatically decreased SERCA ATPase activity and catalase, which removes H2O2, could recover SERCA ATPase activity. Inhibition of ER stress by 4-PBA partially rescued H2O2-induced decreases in SERCA ATPase activity suggesting that this mechanisms can mitigate oxidative stress-induced SERCA impairment. Collectively, these studies provided insight into the cellular mechanisms underlying skeletal muscle dysfunction in ALS and suggest a role for ER stress chaperone proteins in minimizing Ca2+ overload damage in skeletal muscle. These data further suggest that the ER stress pathway could be a novel therapeutic strategy to treat skeletal muscle dysfunction in ALS.Item Alterations in human skeletal muscle proteins in amyotrophic lateral sclerosis(2015) DeRusso, Alicia Lauren; Chin, Eva; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Amyotrophic lateral sclerosis (ALS) is the most common fatal neurodegenerative disease, resulting in loss of voluntary muscle control, atrophy, paralysis, and eventually death. Although the pathophysiology of ALS is not completely understood, recent research in Dr. Chin's lab has identified alterations in skeletal muscle proteins in ALS mice. The purpose of this study was to investigate alterations in proteins involved in calcium handling (SERCA1 and SERCA2), endoplasmic reticulum (ER) stress (Grp78/BiP, PDI, and CHOP) and protein synthesis (Akt) in human ALS skeletal muscle. The ER chaperone protein Grp78/BiP and Akt, a protein involved in protein synthesis, were higher in ALS compared to CON. The calcium pump SERCA1 was lower in diaphragm compared to quadriceps muscles of ALS cases. These data highlight alterations in skeletal muscle proteins not only between ALS and CON, but also between different muscles in ALS, which are helpful for informing future research study designs.Item EXAMINING THE EFFECTS OF EXERCISE ANCESTRY ON TWO GENERATIONS OF MOUSE OFFSPRING(2014) Guth, Lisa Marie; Roth, Stephen M; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)This dissertation research is comprised of three projects examining the effect of voluntary parental exercise on health-related phenotypes in two generations of mouse offspring. We developed a novel model of exercise ancestry where C57BL/6 mice (F0) were exposed to voluntary exercise (EX) or a sedentary (SED) lifestyle and were bred with like-exposed mates to produce first-generation (F1) offspring; F1 offspring were bred with like-exposed offspring to produce second-generation offspring (F2). F0 mice exercised before breeding and continuously through gestation and lactation; all offspring remained sedentary after weaning, thus F0 exercise exposure was the only distinguishing factor between offspring. The first project examined whole body and tissue masses, glucose tolerance, and skeletal muscle gene expression in two generations of 8-week old offspring of exercised vs. sedentary parents. F1 EX females were lighter with less fat mass compared to F1 SED females. F2 EX females had lower baseline blood glucose and impaired glucose tolerance. Further, skeletal muscle lipogenic gene expression was downregulated in females with exercise ancestry, while it was upregulated in males with exercise ancestry. The second study further examined these phenotypes in two generations of adult (28 week) offspring. Parental exercise did not influence offspring body mass or glucose tolerance in 28 week-old offspring, though F1 EX females had higher baseline glucose. Additionally, while some differences in skeletal muscle gene expression were observed, the effect of parental exercise on offspring was blunted at 28 compared to 8 weeks of age. The third study further examined the effects of parental exercise in skeletal muscle as well as adipose and hepatic tissue with regards to metabolite content and gene expression. Exercise ancestry did not affect offspring skeletal muscle or liver triglyceride or glycogen content. Further, there were no effects of exercise ancestry on gene expression levels of glycogen- or triglyceride-related enzymes in skeletal muscle, liver, or adipose tissue. Overall, these studies suggest no adverse effects of parental exercise on metabolic health in multiple generations of mouse offspring.Item Alterations in the myogenic capacity of satellite cells in a mouse model of ALS(2012) English, Samuel A; Chin, Eva R; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a devastating neurodegenerative disease that results in pervasive muscle wasting, paralysis, and ultimately death. Recent research efforts have been made to characterize skeletal muscle in the disease, with some evidence suggesting that the tissue may contribute to ALS pathogenesis. Therefore this study was undertaken to continue to describe ALS skeletal muscle, specifically a population of skeletal muscle-specific stem cells known as satellite cells that play a role in regeneration following injury. Satellite cells were isolated and cultured from mutant mice (SOD1 G93A) that recapitulate the disease, assessed for the capacity to differentiate and proliferate, and compared to age-matched control cultures. SOD1 G93A cultures exhibited decreased expression of transcription factors associated with differentiation (i.e. MyoD and myogenin) compared to control cultures, as well as a reduced ability to proliferate in vitro. These results indicate that the satellite cell population in a mouse model of ALS displays dysfunctional myogenic capacity in vitro, and thus may contribute to the atrophic pathology seen in the disease.Item Association between increased hepatic lipid storage and impaired hepatic mitochondrial function in ovariectomized mice(2012) Valencia, Ana Patricia; Spangenburg, Espen E; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Reduced ovarian function is associated with development of the metabolic syndrome (MetS). Increased risk for MetS is strongly linked to hepatic metabolic dysfunction. However, at this time few studies have examined metabolic function of hepatic tissue under conditions of reduced ovarian function. The purpose of this study was to determine if ovariectomy (OVX) impaired hepatic mitochondrial function and its potential association with sirtuin (SIRT) function. Female C57BL/6 mice were divided into two groups (SHAM, OVX). Hepatic mitochondrial function was measured by assessing oxygen consumption, reactive oxygen species (ROS) production, and mitochondrial protein content. In addition, mitochondrial acetylation status and SIRT protein content was determined. The OVX group exhibited increased ROS production compared to the SHAM group. However, no differences were detected in oxygen consumption, mitochondrial protein content, acetylation status, or total SIRT content between groups. The data shows that ovariectomy increases mitochondrial ROS production, which suggests a novel mechanism to consider.Item TELOMERE DYNAMICS AND REGULATION: EFFECTS OF CHRONIC EXERCISE, ACUTE EXERCISE, AND OXIDATIVE STRESS(2011) Ludlow, Andrew Todd; Roth, Stephen M; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)This dissertation research is comprised of three studies each examining the effects of chronic exercise, acute exercise, or oxidative stress on telomere biology. Exercise training and physical activity have previously been associated with telomere maintenance, but the underlying mechanisms of this association are unclear. The majority of studies to date have been performed in immune cells; however, the findings from these cells may not reflect telomere biology in other tissues. Since exercise is a multi-organ stimulus we sought to describe the effect of exercise on telomere biology in multiple tissues, with a particular focus on skeletal muscle. Study #1 showed that the effect of chronic voluntary exercise on telomere length in CAST/Ei mice is tissue specific. Exercise was `telo-protective' (i.e., maintained telomere length) in cardiac and liver tissues, while telomere shortening was observed in skeletal muscle of exercised animals compared to sedentary and young mice. Study #2 was performed to elucidate the responses to acute exercise that could underlie the paradoxical response of telomere length in skeletal muscle to exercise training. This study revealed that the MAPK pathway appears to be related to the expression of telomere binding proteins in response to acute exercise. In skeletal muscle, p38 MAPK mediated a decrease in gene expression of telomere binding proteins, providing insight into a possible mechanism for eventual telomere shortening in response to chronic exercise. The results of study #2 indicate that the early cellular responses to exercise may accumulate (i.e., repeat bout effect) and underlie the shortened telomere length in skeletal muscle. Study #3 sought to determine if reactive oxygen species were a plausible mechanism of telomere shortening in adult skeletal muscle fibers, as no mechanism to date has been elucidated for telomere shortening in this tissue. Study #3 showed that oxidative stress is a potent telomere- shortening stimulus in skeletal muscle fibers of mice and that telomere binding protein expression was also significantly affected by oxidative stress. In total these results indicate that although chronic exercise attenuates telomere shortening in most tissues, skeletal muscle demonstrates a unique contradictory response likely due to its reaction to oxidative stress.