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Chronic stress elicits sex-specific mitochondrial respiratory functional changes in the rat heart
Thesis (MSc)--Stellenbosch University, 2023.
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| Format: | Thesis |
| Language: | English |
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Stellenbosch : Stellenbosch University
2023
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| _version_ | 1867613737675915264 |
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| access_status_str | Open Access |
| author | Odendaal, Caitlin Paige |
| author2 | Essop, M. Faadiel
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| author_browse | Essop, M. Faadiel
Odendaal, Caitlin Paige |
| author_facet | Essop, M. Faadiel
Odendaal, Caitlin Paige |
| author_sort | Odendaal, Caitlin Paige |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (MSc)--Stellenbosch University, 2023. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/129353 |
| institution | Stellenbosch University (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:40:54.381Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2023 |
| publishDateRange | 2023 |
| publishDateSort | 2023 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/129353 Chronic stress elicits sex-specific mitochondrial respiratory functional changes in the rat heart Odendaal, Caitlin Paige Essop, M. Faadiel Joseph, Danzil Maarman, Gerald Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Division of Medical Physiology. Stress (Physiology) Mitochondrial pathology Sex differences UCTD Thesis (MSc)--Stellenbosch University, 2023. ENGLISH ABSTRACT: The term ‘stress’ has become ubiquitous with the day-to-day activities of contemporary society and is a prominent contributor to downstream pathologies such as the onset and progression of cardiometabolic diseases. Despite its prevalence, psychosocial stress remains an elusive concept that has intrigued the minds of physiologists, psychologists, and physicians since the twentieth century. Due to its significant implications for health and wellness, there is a growing body of modern research focusing on gaining greater insights regarding the etiology and mechanisms driving stress-related cardiometabolic complications. Although the underlying mechanisms remain unclear, the intrinsic need for complex signaling and cellular energy at all levels of the stress response places the mitochondrion at the nexus of disease. We therefore hypothesize that dysregulated mitochondrial function may be a putative mediator in stress-related cardiac pathologies. We investigated this hypothesis using a pre-clinical chronic restraint stress (CRS) rat model completed in a sex-dependent manner as there is a dearth of scientific knowledge relating to females. Here, the CRS model was applied to 10-week-old male (n=8 control; n=8 stress) and female (n=8 control; n=8 stress) Wistar rats, i.e., one hour daily for 4 weeks with a consecutive week of rest, mimicking an anxious phenotype. Mitochondrial respiration parameters were thereafter evaluated on isolated medium-free-frozen heart tissue using high-resolution respirometry. Western blotting analyses were completed to gain insights regarding cardiac mitochondrial fission, fusion, biogenetic, and respiratory proteins. We also completed several oxidative stress assays to evaluate the redox status of the heart in response to chronic stress. Additionally, plasma and serum samples were collected prior- to and post-CRS for analyses of circulating sex and stress hormones, whereas elevated plus maze (EPM) and tail-flick (TF) tests were performed to assess the degree of psychosocial stress. The main findings of this thesis were the following: i) chronic stress elicited distinct sex-based differences in mitochondrial respiratory function and regularity proteins and ii) mitochondrial perturbations represent early cellular changes in response to stress. Despite the limited changes in behavior or circulating stress hormones, stressed males exhibited a decrease in oxidative phosphorylation via both ß-oxidation and glucose oxidation respiratory pathways that were not due to uncoupling. They also displayed an increased myocardial antioxidant capacity compared to their control counterparts. Conversely, stressed female rats displayed no changes in respiratory functional or oxidative stress parameters despite lowered circulating estradiol levels. Further investigation revealed an upregulation of myocardial complex I, III, and ATP synthase protein levels in females while males displayed increased ATP synthase levels. Stressed males also displayed attenuated peroxisome proliferator-activated receptor-gamma coactivator 1-α (PGC-1α) protein levels (master regulator of mitochondrial biogenesis), while a decrease in the Drp1 (fission protein) was uniform across both stressed sexes. Collectively, our results emphasize the pivotal role of the mitochondrion as a sex-dependent rheostat in response to chronic stress. Here, males were more prone to stress-related mitochondrial functional changes, while the females exhibited a more protective and resilient phenotype. AFRIKAANSE OPSOMMING: Die term 'stres' het algemeen geword met die daaglikse aktiwiteite van die hedendaagse samelewing en is 'n prominente bydraer tot stroomaf patologieë soos die aanvang en progressie van kardiometaboliese siektes. Ondanks die voorkoms daarvan, bly psigososiale stres 'n ontwykende konsep wat sedert die twintigste eeu die gedagtes van fisioloë, sielkundiges en dokters gefassineer het. Weens die beduidende implikasies vir gesondheid en welstand, is daar 'n toenemende hoeveelheid moderne navorsing wat fokus op die verkryging van groter insigte rakende die etiologie en meganismes wat stresverwante kardiometaboliese komplikasies aandryf. Alhoewel die onderliggende meganismes onduidelik bly, plaas die intrinsieke behoefte aan komplekse sein en sellulêre energie op alle vlakke van die stresrespons, die mitochondrion by die verband van siektes. Ons hipotiseer dus dat gedisreguleerde mitochondriale funksie 'n vermeende bemiddelaar in stresverwante hartpatologieë kan wees. Ons het hierdie hipotese ondersoek met behulp van 'n pre-kliniese chroniese inperkingsstres (CRS) rotmodel wat op 'n geslagsafhanklike manier voltooi is, weens 'n gebrek aan wetenskaplike kennis met betrekking tot vroue is. Hier is die CRS-model toegepas op 10 weke oue mannetjie (n=8 kontrole; n=8 stres) en wyfie (n=8 kontrole; n=8 stres) Wistar rotte, dit wil sê een uur per dag vir 4 weke met 'n opeenvolgende week van rus, wat 'n angstige fenotipe naboots. Mitochondriale respirasieparameters is daarna op geïsoleerde mediumvrye bevrore hartweefsel geëvalueer met behulp van hoë resolusie respirometrie. Westerse blotting-ontledings is voltooi om insigte te verkry rakende hart mitochondriale splitsing, samesmelting, biogenetiese en respiratoriese proteïene. Ons het ook verskeie oksidatiewe strestoetse voltooi om die redoksstatus van die hart in reaksie op chroniese stres te evalueer. Daarbenewens is plasma- en serummonsters voor- en na-CRS versamel vir ontledings van sirkulerende seks- en streshormone, terwyl verhoogde plus doolhof (EPM) en stertflikker (TF) toetse uitgevoer is om die mate van psigososiale stres te bepaal. Die belangrikste bevindings van hierdie tesis was die volgende: i) chroniese stres het duidelike geslagsgebaseerde verskille in mitochondriale respiratoriese funksie en regulatoriese proteïene ontlok en ii) mitochondriale versteurings verteenwoordig vroeë sellulêre veranderinge in reaksie op stres. Ten spyte van die beperkte veranderinge in gedrag of sirkulerende streshormone, het gestresde mannetijies 'n afname in oksidatiewe fosforilering deur beide -oksidasie- en glukoseoksidasie-respiratoriese weë getoon wat nie te wyte was aan ontkoppeling nie. Hulle het ook 'n verhoogde miokardiale antioksidantkapasiteit getoon in vergelyking met hul kontrole-eweknieë. Wyfie rotte het die teenoorgestelde getoon, met geen beduidende veranderinge in respiratoriese funksionele of oksidatiewe stresparameters nie, ondanks verlaagde sirkulerende estradiolvlakke. Verdere ondersoek het 'n opregulering van miokardiale kompleks I, III en ATP sintase proteïenuitdrukking by wyfies aan die lig gebring, terwyl mannetjies verhoogde ATP-sintasevlakke vertoon het. Gestresde mannetjies het ook verswakte peroksisoom proliferator-geaktiveerde reseptor-gamma koaktivator 1- (PGC-1) proteïenvlakke (meesterreguleerder van mitochondriale biogenese) vertoon, terwyl 'n afname in die Drp1 (splitsingsproteïen) uniform was oor beide gestresde geslagte. Gesamentlik beklemtoon die resultate die deurslaggewende rol van die mitochondrion as 'n seksafhanklike reostat in reaksie op chroniese stres. Hier was mannetjies meer geneig tot stresverwante mitochondriale funksionele veranderinge, terwyl die wyfies 'n meer beskermende en veerkragtige fenotipe vertoon het. Masters 2023-11-12T19:36:36Z 2024-02-20T08:36:42Z 2023-11-12T19:36:36Z 2024-02-20T08:36:42Z 2023-11 Thesis https://scholar.sun.ac.za/handle/10019.1/129353 en Stellenbosch University xvi, 139 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Stress (Physiology) Mitochondrial pathology Sex differences UCTD Odendaal, Caitlin Paige Chronic stress elicits sex-specific mitochondrial respiratory functional changes in the rat heart |
| title | Chronic stress elicits sex-specific mitochondrial respiratory functional changes in the rat heart |
| title_full | Chronic stress elicits sex-specific mitochondrial respiratory functional changes in the rat heart |
| title_fullStr | Chronic stress elicits sex-specific mitochondrial respiratory functional changes in the rat heart |
| title_full_unstemmed | Chronic stress elicits sex-specific mitochondrial respiratory functional changes in the rat heart |
| title_short | Chronic stress elicits sex-specific mitochondrial respiratory functional changes in the rat heart |
| title_sort | chronic stress elicits sex specific mitochondrial respiratory functional changes in the rat heart |
| topic | Stress (Physiology) Mitochondrial pathology Sex differences UCTD |
| url | https://scholar.sun.ac.za/handle/10019.1/129353 |
| work_keys_str_mv | AT odendaalcaitlinpaige chronicstresselicitssexspecificmitochondrialrespiratoryfunctionalchangesintheratheart |