School of Public Health
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The collections in this community comprise faculty research works, as well as graduate theses and dissertations.
Note: Prior to July 1, 2007, the School of Public Health was named the College of Health & Human Performance.
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Item Excitation-Contraction Coupling Disruption in a Mouse Model of Niemann-Pick Disease(2017) Li, Harry Zichen; Chin, Eva R; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Niemann-Pick disease (NPD) is a lysosomal storage disorder that results from deficient acid sphingomyelinase (ASM) activity. It was recently proposed that ASM and extracellular Ca2+ are required for membrane repair. Since plasma membrane integrity is an important component of excitation-contraction coupling (E-C) and skeletal muscle force production, we hypothesized that there would be E-C coupling defects in NPD related to intracellular calcium (Ca2+) dynamics. Our results demonstrate that ASM deficient (ASM-/-) fibers have a reduced ability to withstand repetitive contractions in comparison to wild-type (WT) fibers, and fibers from ASM-/- mice exhibited lower peak tetanic Ca2+ compared to WT. Lastly, no differences in peak tetanic Ca2+ were found between ASM-/- fibers and WT fibers deprived of Ca2+. Together, these results suggest that both ASM and extracellular Ca2+ are required for optimal E-C coupling in skeletal muscle and for the ability to respond to repetitive contractions that occurs with sustained activity.Item EFFECTS OF CARDIOVASCULAR DISEASE AND PHYSICAL INACTIVITY ON THE PARACRINE FUNCTION OF CIRCULATING ANGIOGENIC CELLS(2015) Landers-Ramos, Rian Quinn; Hagberg, James M; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Cardiovascular disease (CVD) is the leading cause of death in developed countries. Traditional cardiovascular risk factors account for only a fraction of events related to CVDs, emphasizing the need for investigations into more novel risk factors. Circulating angiogenic cells (CACs) are involved in the repair and maintenance of the vascular endothelium and function mainly through paracrine mechanisms. The studies presented in this dissertation provide new insight into differences in the paracrine actions of CACs as a function of habitual physical activity and CVD. The first study presented identifies, for the first time, that secreted factors from CD34+ and CD34-/CD31+ CACs affect HUVEC tube formation as a function of habitual physical activity. Study #1 identifies inflammatory proteins S100A8 and S100A9 as major factors contributing to the depressed tube formation observed when using CD34-/CD31+ conditioned media (CM) from inactive younger adults compared to endurance-trained athletes. The second study aimed to confirm the effects of S100A8 and S100A9 in CD34-/CD31+ CM on HUVEC tube formation in CVD patient populations compared to endurance-trained athletes. Study #2 found that the CM from non-ST- segment elevation myocardial infarction (NSTEMI) patient CD34-/CD31+ CACs impaired tube formation compared to athletes’ CM, and that pretreatment of HUVECs with an inhibitor for TLR4, a major receptor for S100A8 and S100A9, rescued tube formation to the levels observed when using CD34-/CD31+ CM from athletes. Higher S100A8 and S100A9 content was found in the CM of NSTEMIs compared to athletes. Finally, the study #2 mechanistically demonstrated the direct role of S100A8 and S100A9 on tube formation using recombinant S100A8 and S100A9 and confirmed that these actions were mediated by TLR4. Preliminary data in study #2 suggest that cell surface markers on selected CD34-/CD31+ CACs are inherently different between NSTEMI patients and endurance-trained athletes with lower presence of T-cell and monocyte markers on the CD34-/CD31+ CACs of NSTEMI patients. Collectively, the two studies presented in this dissertation demonstrate that both physical inactivity and CVD alter the paracrine actions of CD34-/CD31+ CACs which in turn impair HUVEC tube formation. These findings are of particular importance as new methods to improve CAC function for therapeutic purposes are being developed.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 The Effect of Metabolic Substrate on ROS Production During Muscle Contraction(2015) Amorese, Adam James; Spangenburg, Espen; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Many different disease states are characterized by mitochondrial dysfunction, which results in excessive reactive oxygen species (ROS) production. In contrast muscle contraction induces ROS generation suggesting there is an optimal range of ROS production necessary for proper cell function. It is unclear if ROS production is influenced by metabolic substrate flux as a result of the energetic demand of contraction. The purpose of this study was to determine the rate and source of ROS production in contracting single muscle fibers (SMF) cultured with different metabolic substrates. ROS production was assessed in SMF isolated from adult male mice exposed to different stimulation conditions and/or different sources of metabolic substrate. Mitochondrial membrane potential was also assessed in SMF under similar conditions. The results of this study demonstrate ROS generation is significantly influenced by metabolic substrate and larges increases in ROS do not affect mitochondrial membrane potential in intact SMF.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.Item REGULATORY EFFECTS OF ACUTE AND CHRONIC ENDURANCE EXERCISE ON NITRIC OXIDE AND REACTIVE OXYGEN SPECIES IN HUMAN CIRCULATING ANGIOGENIC CELLS(2011) Jenkins, Nathan Thomas; Hagberg, James M; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)This dissertation research comprised three studies examining the effects of acute and chronic endurance exercise on circulating angiogenic cells (CACs). Because the balance between nitric oxide (NO) and reactive oxygen species (ROS) is a critical aspect of the physiological function/dysfunction of CACs, each study determined the effects of exercise on NO-ROS balance within a variety of CAC types. Study #1 demonstrated that regular endurance exercise is associated with greater basal intracellular NO levels in cultured CACs, and that one mechanism underlying this association was increased NADPH oxidase enzyme activity in the sedentary state. Study #2 suggested an association between a sedentary lifestyle and increased nitro-oxidative stress in freshly-isolated CD34+ progenitor cells. Study #3 demonstrated that prior exercise attenuates high-fat meal induced-increases in mitochondrial-derived intracellular ROS in CD31+ CACs. Overall, it is concluded that acute and chronic endurance exercise enhance intracellular NO and ROS dynamics in CACs.