School of Public Health
Permanent URI for this communityhttp://hdl.handle.net/1903/1633
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.
Browse
4 results
Search Results
Item Cardiac Mitochondrial Function and Exertional Tolerance in a Rat Model of Pressure-Overload Induced Heart Failure(2022) Li, Harry Zichen; Kuzmiak-Glancy, Sarah; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Heart failure (HF) is characterized by the inability of the heart to provide adequate cardiac output to meet their body’s demand for fuel and oxygen, particularly during periods of exertion. In fact, a hallmark characteristic of HF is exertional intolerance where performing activities brings about, or exacerbates, symptoms of dyspnea and/or fatigue. This exercise intolerance has been attributed to altered cardiac and skeletal muscle function. The myocardium of the heart is reliant upon cardiac mitochondria to generate sufficient ATP to fuel this highly metabolically active tissue. Therefore, reduced mitochondrial ATP production may play a role in myocardial dysfunction and contribute to reduced cardiac output in HF. Mitochondria react to intracellular signals to respond to energetic demands, and therefore, mitochondrial function is a product of both the mitochondria itself and the environment in which it resides. Intracellular Ca2+ and Na+ are of particular interest as they play a role in regulating mitochondrial function and the intracellular concentrations are elevated in ventricular myocytes in HF. Therefore, a goal of these investigations was to evaluate how altered Na+ and Ca2+ can impact the ability of cardiac mitochondria to respond to an increase in demand in mitochondria isolated from young healthy rat hearts, as well as rats with pressure-overload induced HF. A second goal of these investigations was to determine if pressure-overload induced heart failure altered exercise capacity, as well as in vivo and ex vivo skeletal muscle strength. In the first study, mitochondria were isolated from the ventricular tissue of young, healthy male rats, and oxygen consumption and mitochondrial activation by Ca2+ was assessed in the presence of elevated Na+ to mimic the cellular environment of HF. Ca2+ effectively activated mitochondrial ATP production, despite elevated Na+, suggesting that the ionic conditions of HF ventricular myocytes alone are not sufficient to disrupt mitochondrial function. In the second study, mitochondrial function was assessed under the same ionic conditions as the previous study, however, mitochondria were isolated from male rats with pressure-overload induced hypertrophy or sham-operated controls. Ca2+ was able to activate mitochondrial function regardless of Na+ concentration in both HF and sham mitochondria; however, failing mitochondria exhibited depolarized mitochondrial membrane values across these respiration rates, implicating an impaired potential for ATP production in failing ventricular mitochondria. In the third study, HF and sham male and female rats were evaluated for their exertional tolerance, and the results indicated that HF rats tolerated treadmill running and showed no deficits in grip exercise; however, solei muscle from female heart failure rats exhibited diminished contractile capacity, suggesting female skeletal muscle may respond differently than male skeletal muscle to heart failure. These findings indicate that failing mitochondria may be intrinsically dysfunctional regardless of an altered ionic environment and that there may be sexual dimorphism in the skeletal muscle function and its role in exercise intolerance in HF.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 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 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.