Kinesiology & Health Science

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Open Access
Multi-Method Study On Referral And Access To Heart Function Clinics
(2025-04-10) Mamataz, Taslima; Grace, Sherry
Patients with heart failure (HF) experience significant benefits from receiving comprehensive outpatient care in specialized heart failure clinics (HF clinics). These clinics have demonstrated their effectiveness in reducing frequent HF-related hospital readmissions while maintaining cost-efficiency. Unfortunately, despite established guidelines recommending the referral of HF patients to these clinics, there exists a notable discrepancy in both access and utilization of this specialized care, creating issues of low and inequitable service utilization. The underlying reasons are largely unknown and under-researched. Therefore, this doctoral dissertation aimed to advance a scholarly understanding of factors influencing the referral decisions and access to HF clinics through a multi-method study. For this purpose, three inter-linked research studies were undertaken. Firstly, qualitative interviews were conducted with key stakeholders in HF care, including policymakers, clinic providers, and patients. This initial phase established a foundational understanding of the barriers preventing optimal access to HF clinic services. Secondly, recognizing that referring providers play a pivotal role in determining patient access to HF clinics, a mixed-method design was employed, using a sequential exploratory approach to delve into their perspectives on the challenges associated with referring patients to HF clinics. Finally, a cross-sectional survey approach was adopted to compare clinic perceptions of ideal referral criteria with those of referring providers. By identifying areas of agreement between both parties, strategies for consistent application were proposed. This dissertation contributes valuable insights for HF clinics and the broader HF community. The knowledge generated has the potential, when translated into practice, to facilitate appropriate patient access to essential HF services. The findings offer guidance to policymakers, healthcare providers, and HF patients, aiming to optimize the utilization of HF clinic services, enhance the quality of care provided, and improve overall patient outcomes.
Open Access
The Effects Of Age And Distraction On Interlimb Synchronization Of The Center Of Pressure
(2025-04-10) Jalalipour, Arash; Mochizuki, George
Older adults experience increased fall risk, which may be influenced by distractibility. This study examines the effects of cognitive distractions on interlimb synchronization and balance in young and older adults. Participants performed quiet standing trials on separate force plates under eyes-open and eyes-closed conditions, with and without cognitive distraction (counting by ones, backward by sevens). Interlimb synchrony was assessed using cross-correlation (CCF) of center of pressure (COP) movements, while root mean square (RMS) sway and mean sway velocity (MSV) were also analyzed. It was hypothesized that cognitive distractions would reduce synchrony, particularly in older adults. Results showed no significant differences in CCF or RMS across groups or conditions, but MSV varied significantly across conditions. These findings suggest that while cognitive distractions affect postural sway velocity, they do not significantly impact synchrony or RMS under these conditions. This study enhances our understanding of balance-cognition interactions in aging.
Open Access
Sex Differences In Endothelial FoxO1 Response To Nutrient And Oxidative Stress
(2025-04-10) Nahal, Manvir Singh; Tara Haas
Endothelial cells (ECs) are vital for vascular homeostasis, regulating blood flow, nutrient exchange, and immune responses. EC dysfunction contributes to diseases such as type 2 diabetes, atherosclerosis, and hypertension, with sex-specific differences in disease progression. Our lab previously observed sex differences in the response of adipose tissue ECs (ATECs) to high-fat diet-induced metabolic and oxidative stress, with females showing more favorable outcomes. Female ECs express higher Forkhead Box O1 (FoxO1) levels than males, suggesting sex-specific FoxO1 regulation. To explore this, male and female ECs were exposed to metabolic and oxidative stress, and FoxO1 subcellular localization and post-translational modifications were assessed. Male ECs showed increased FoxO1 phosphorylation and cytoplasmic localization, while females retained FoxO1 in the nucleus, supporting enhanced transcriptional potential. These findings highlight sex-dependent FoxO1 regulation, offering insights into molecular mechanisms driving sex differences in vascular health.
Open Access
Relationships Between Movement Behaviours And Dementia
(2025-04-10) Oye-Somefun, Akinkunle Olayemi; Ardern, Chris
The primary objectives of this dissertation were three-fold: i) to evaluate the association of movement behaviors on incident dementia through a systematic review and meta-analysis; ii) to examine the association of movement behaviors on 3-year changes in memory among middle-aged and older adults, stratified by sex; and iii) to investigate the sex-specific association between movement behaviors on cognitive function changes over three years, including the mediation effects of cardiovascular disease on cognitive function. Data from population-based cohort studies, including the Canadian Longitudinal Study of Aging (CLSA), were utilized. A systematic review and meta-analysis (SRMA), as well as general linear regression, and mediation analyses, were employed. In SRMA Study 1, regular physical activity was associated with a 28% reduction in the risk of incident dementia, while both short (<7 hours) and long (>8 hours) sleep durations were associated with an increased dementia risk (RR = 1.23 and 1.32, respectively). In CLSA Studies 2 and 3, 6-8 hours of sleep was associated with positive changes (z-scores) in immediate and delayed recall among males. Among females, the interaction of higher physical activity levels (≥10 MET-hours weekly) with 8+ hours of sleep and high sedentary time led to an increase in delayed recall. Increasing sedentary time was associated with positive changes in cognitive function in males, while excessive sleep duration was associated with a negative change in cognition. Sitting time was found to mediate the relationship between cardiometabolic components and cognitive changes over three years among males (negatively: systolic blood pressure, high-density lipoprotein, carotid intima-media thickness, glycosylated haemoglobin, and positively: waist circumference, diastolic blood pressure, and triglycerides) but not females. The relationship between sitting time and 3-year change in global cognition was further mediated through waist circumference and high-density lipoprotein among both females and males, while glycosylated hemoglobin mediated the sitting time and cognition relationship among males but not females. This dissertation highlights the importance of optimizing movement behaviors for cognitive health among older adults, emphasizing the opportunity for targeted interventions to reduce dementia risk and enhance overall cognitive functioning.
Open Access
Biological Ageing Of Skeletal Muscle Endothelial Cells & Responsiveness To Vegf-A: Role Of Epigenetic Writer Ezh2
(2025-04-10) Essue, Dayna Olivia; Roudier, Emilie
In the older population, the loss of small blood vessels (capillaries), known as rarefaction, precedes muscle atrophy. Aging alters the capacity of endothelial cells, the main constituents of capillaries, to form new blood vessels through angiogenesis. Epigenetics has emerged as a new research area to uncover how an ageing phenotype is acquired. Through this project we investigate how the epigenetic writer Enhancer of Zeste Homologue 2 (EZH2) regulates the pro-angiogenic pathway downstream of vascular endothelial growth factor-A (VEGF-A) and its receptor 2 (VEGFR-2) in skeletal muscle microvascular endothelial cells (SMECs) using an in-vitro model of aging. Our results suggest that EZH2 activity might restrain angiogenesis by impairing the expression of genes downstream of the VEGF-A pathway, such as Nr4a3 and Egr3. Our findings indicate that EZH2 potentially supports vascular aging. Yet, caution is required as in-vitro models, such as passaging, fails to reproduce all aspects of aging, more particularly senescence in primary cells
Open Access
Investigating Metabolic And Inflammatory Relationships In Two Distinct Models Of Right-Sided Cardiac Stress
(2025-04-10) Gandhi, Shivam; Perry, Christopher
This thesis summarizes data generated from two distinct models with unrelated underlying etiology that both implicate metabolic- and inflammatory-mediated adaptations in right-sided cardiac stress. The first model, Duchenne muscular dystrophy (DMD), is a neuromuscular disease caused by mutations in the X-linked DMD gene that encodes the sub-sarcolemmal protein, dystrophin. While current standards of care –glucocorticoid administration and gene-editing therapies – provide promise for skeletal muscle impairments, the effects of these interventions on dystrophic cardiomyopathy are unclear. The purpose of this thesis was to characterize chamber-specific remodeling in young D2.B10-DMDmdx/2J (D2.mdx) mice, while concurrently exploring if an adiponectin peptidomimetic (ALY688) could alleviate underlying chamber-specific pathology. Our results demonstrated that right ventricular (RV) fibrosis and cardiomyocyte hypertrophy in 4-week-old D2.mdx mice were related to lower mitochondrial respiration and increased complex I-stimulated mitochondrial H2O2. ALY688 prevented RV fibrosis and cardiomyocyte hypertrophy, concurrent with macrophage sub-population shifts towards an anti-inflammatory phenotype. Our findings identified that the dystrophic heart is heterogeneously affected, while ALY688 represents a viable intervention aimed at addressing secondary contributors to dystrophic cardiac remodeling. The second model, on-pump coronary artery bypass grafting (CABG) surgery, is a common intervention for treatment of coronary artery disease. Key to this surgery is infusion of cardioplegia, which temporarily arrests the heart so surgeons can anastomose grafts around occluded coronary arteries while blood supply is maintained by cardiopulmonary bypass. The combination of ischemia and reperfusion remains a precipitator of post-operative complications. To date, repeated-measures mitochondrial stress responses associated with CABG have never been explored in a study design that compares right atrial appendage (RAA) samples from the same patient at multiple time-points. Therefore, the purpose of this study was to investigate if post-CABG RAA exhibited alterations to mitochondrial stress responses (perturbed mitochondrial substrate-specific respiration and reactive oxygen species (ROS)-mediated protein adaptations) that correlated with patient discharge times. Preliminary findings demonstrated that CABG is associated with increased fatty acid-supported respiration on the post-CABG RAA. It is unknown if this is a protective mechanism or a detrimental mitochondrial stress response. Correlative statistics suggest that the increase in fatty acid-supported respiration and ROS-mediated adaptations do not improve patient discharge times.
Open Access
Characterizing The Role Of Sulforaphane In Mitochondrial Function And Content In Skeletal Muscle Cells
(2024-11-07) Champsi, Sabrina; Hood, David
A healthy mitochondrial reticulum is critical for the maintenance of skeletal muscle. Preservation of the pre-existing pool through the antioxidant response and synthesis of new mitochondria (biogenesis) ensures the quality and quantity of mitochondria is sustained. Exercise has been established an effective intervention to enhance the mitochondrial phenotype, since it elicits metabolic alterations which drive these quality control processes. To evaluate if a pharmaceutical intervention may be able to mimic or enhance exercise induced-mitochondrial adaptations, the compound sulforaphane (SFN) was examined. SFN has been reported as a potent activator of the nuclear factor erythroid 2-related factor 2 (Nrf-2) signaling cascade which enhances the expression of antioxidant and cytoprotective-related genes. Although activation of this signaling cascade has proven to be beneficial, its relevance to mitochondria has not been fully understood. To investigate this, SFN was combined with an in vitro model of “exercise” and mitochondrial parameters were examined. Our results suggests that SFN activates pathways that elicit exercise-induced mitochondrial adaptations.
Open Access
The Influence of Oral Contraceptives on the Autonomic Nervous System
(2024-11-07) Pereira, Tania De Jesus; Edgell, Heather
This thesis aims to determine the effects of oral contraceptives (OC) on resting autonomic function, autonomic reflex activation, and cerebral blood flow (CBF). The first study systematically reviewed the effects of OC on any aspect of autonomic function. A search strategy was applied to several databases, and 6,148 citations were retrieved. Forty studies were included and grouped by measurement of autonomic function investigated. Physiological responses to isolated reflex activation (i.e., the chemoreflex, mechanoreflex and metaboreflex) were influenced by OC; however, the effect of OC on resting autonomic indices and response to autonomic stressors was less consistent. These inconsistencies may be caused by hormone dosage within OC formulations or stressor intensity. The second study investigated the influence of OC on the cardiorespiratory response to metabo- and mechanoreflex activation in the arm and leg. Two minutes of isometric handgrip or plantarflexion exercise-induced similar increases in blood pressure (BP) and ventilation (VE) in both OC and non-OC users (NOC). While both exercise modalities increased VE, neither OC nor NOC exhibited a sustained increase in VE during 3 minutes of arm or leg post-exercise circulatory occlusion. All women increased BP and VE during 3 minutes of arm or leg passive movement. Considering that all women had a cardiorespiratory response to mechanoreflex but not metaboreflex activation, we suggest that the mechanoreflex may drive VE during exercise in women. The final study investigated the influence of OC and the menstrual cycle on CBF and cerebral autoregulation (CA) during 5 minutes of hypercapnia (5%). Regardless of menstrual or pill phase, all women improved high frequency and very low frequency dynamic CA (dCA) during hypercapnia, although low frequency dCA decreased in the high hormone phase of NOC and the low hormone phase of the pill cycle. During hypercapnia, the presence of endogenous hormones attenuated dCA, while the chronic use of exogenous hormones (i.e., OC) chronically attenuated dCA (i.e., when hormones were not present). The findings of this thesis shed light on the complex influence of OC on autonomic function, CBF and different physiological stressors, emphasizing the need for further research to fully elucidate its impact. There is a further need to control for menstrual cycle, OC formulation, dose, progestin generation and/or type when studying factors affecting autonomic physiology.
Open Access
An Exploration of Stress Reactivity and Mindfulness Meditation in Individuals with Migraine Utilizing Heart Rate Variability
(2024-11-07) Mohabir, Vinashini Saraswatty Devi; Ritvo, Paul G.
Headaches are associated with autonomic nervous system imbalance reflected in heart rate variability (HRV). Mindfulness Meditation (MM) is an evidence-based tool for regulating HRV. Previous literature has examined HRV changes in those with headache disorders after cognitive stress induction. These studies have found there were significant increases in HRV after stress induction in those that practiced MM. The current study examined HRV changes in migraineurs. Participants (N=26) were randomly assigned to a 10-minute recovery condition involving guided MM Practice (N=13) or listening to a description of MM (N=13) following cognitive stress induction. A between-subjects repeated measures MANOVA found a significant difference in HF-HRV over time that varied based on the meditation condition. There was also a significant change in respiratory rate over time regardless of condition. Additional research should be completed with migraineurs to understand ANS activity in migraine and the mechanisms of MM in this population
Open Access
Addictive Tendencies Towards Food: A Multi-Method Analysis of ‘Food Addiction’ and Related Psychopathologies
(2024-11-07) Bonder, Revi; Davis, Caroline
This dissertation comprises two sequential multi-method studies: a quantitative followed by a qualitative study. The primary aim of the first study was to confirm our previous research examining compulsive grazing in a clinical population with obesity and a higher prevalence and severity of food addiction (FA). Moderating effects of weight and sex on the severity and frequency of FA were also explored. Adults with obesity (aged 20 to 50 years) were recruited from a weight-management clinic (n=437). Participants completed an online questionnaire assessing various eating behaviours and related personality measures. Multiple and logistic regression modelling were used with the Yale Food Addiction Scale symptom count and diagnosis as the dependent variables, respectively. A chi-square test of independence and an analysis of variance were used to determine sex differences. Compulsive grazing was a significant factor in FA diagnosis and symptom severity, confirming previous findings. Females from a weight-management clinic sample were more likely to receive an FA diagnosis than females from the general population. The purpose of the second study was three-fold: 1) to explore perceptions of compulsive grazing in individuals with overweight and obesity; 2) to understand where compulsive grazing fits within the spectrum of overeating, particularly in relation to FA; and 3) to assess if the FA concept reflects participants’ experiences. Females (n=34) from the first study were recruited and interviewed virtually using semi-structured interviews. Interviews were transcribed verbatim. A flexible coding system was developed, which led to a final list of three categories. Notably, findings indicated varied eating behaviours among those with FA (binge eating, compulsive grazing, or a combination of both). Accordingly, a new conceptualization of FA was proposed. Lastly, participants identified bariatric surgery and pharmacologic treatments as effective for managing cravings and compulsive eating. Overall, this dissertation provided a holistic understanding of FA and its associated behaviors. This dissertation contributes to the increasing recognition of FA as a genuine substance-use disorder, which can hopefully have an impact on public health by reducing obesity stigma and enhancing treatment access for individuals with FA.
Open Access
The effects of learning schedules and external visual information on implicit sensorimotor adaptation of upper limb movements.
(2024-11-07) Modchalingam, Shanaathanan; Henriques, Denise
Implicit motor adaptation is vital for maintaining accurate movements when faced with changes in the environment or our own bodies. Using both simple and complex motor tasks, this dissertation investigates the limits of implicit adaptation in upper-limb motor adaptation, and its sensitivity to visual context cues. We first demonstrate that the extent of implicit adaptation depends on how motor errors are introduced during a training paradigm. We find the largest extents of implicit adaptation when participants can adapt to small but noticeable motor errors before experiencing further perturbations to their movements. This method of error introduction led to significantly larger adaptation compared to both abruptly introducing large errors or introducing small errors in a ramped manner. Next, we determined that when adapting to opposing perturbations simultaneously, task-relevant object-shape cues that predict the presence of a given perturbation are insufficient to consistently trigger the formation of object-specific motor memories. Finally, we show that when perturbations can plausibly assign the source of errors to environment causes, context-dependent motor learning can readily occur. Overall, this dissertation highlights the adaptability of implicit motor learning, emphasizing the need to consider perturbation methods, contextual influences, and task complexity when designing effective motor learning paradigms.
Open Access
Effects Of Cold-Water Immersion On Post-Exercise Skeletal Muscle Recovery Following Sprint-Interval Exercise
(2024-10-28) Richards, Andrew Jason; Cheng, Arthur
Cold-water immersion has emerged as a popular post-exercise recovery intervention for athletes and avid exercisers. However, little evidence exists to support its widespread use, especially following high-intensity interval exercise (HIIE). Therefore, to investigate the use of CWI following HIIE, 12 participants participated in a randomized cross-over study involving repeated all-out contractions of the ankle dorsiflexor muscles followed by CWI or room temperature rest (RT). During a 24-h recovery period, neuromuscular function, intramuscular temperature, and next-day HIIE were performed. The results of the study showed that CWI impaired maximal tetanic force for up to 3-h, whereas immediate recovery occurred following RT. In addition, there was no difference in next-day HIIE performance between the two recovery interventions. Thus, CWI offers no substantial benefit as an effective post-exercise recovery intervention following HIIE.
Open Access
Effects of Manipulating Optic Flow Gain on Dynamic Postural Control During Continuous Support Surface Translations
(2024-07-18) Laurenza, Daniel Alon; Cleworth, Taylor
Human postural control involves interactions between visual, vestibular, and somatosensory systems to maintain upright stance. Quiet stance assesses posture when participants are standing still, and dynamic postural control has been assessed through use of moveable support surfaces. Limited work utilizes VR-induced optic flow with continuous platform translations to examine balance. SS oscillations perturbed participants in the A-P direction. Kinetic and kinematic information was quantified into center-of-pressure, center-of-mass, and joint and segment angles. We observed that as gain values increased, participants experienced a relative decrease in sway amplitude, and increases in both sway frequency and velocity, reflecting a tighter regulation of stance with greater visual information. These changes were generally more evident in the second minute of trials. By further examining dynamic postural control and its relationship with optic flow through VR, this thesis demonstrated the effectiveness of utilizing visual information to impact postural behaviours in young, healthy adults.
Open Access
Are We Oppressed or Liberated or Both? A Case Study of Persian Women Medical Doctors in Ontario
(2024-07-18) Fouladirad, Tanaz; Nakamura, Yuka
This study focuses on Persian women medical doctors and their lived experiences of immigrating to and settling in Canada, with particular focus on how they came to work as medical doctors in Ontario, and how these experiences shaped their gendered and racialized identities. Drawing on post-colonial feminist theory, this thesis entails a case study, where data were collected through (1) semi-structured interviews with Persian women medical doctors and (2) textual analysis of Canada’s Immigration and Citizenship website and documents pertaining to professional accreditation and credentialling. The findings illustrate the study participants were able to successfully immigrate to Canada via the points system because of their education, training as medical doctors, and English language skills, having been educated in English. However, upon arrival, these same resources constrained settlement. In response, the women in this study exercised their agency and resisted stereotypes of being docile, submissive, and complacent Muslim women.
Open Access
Branched-Chain Amino Acid Catabolism: Regulation and Effect on Insulin Resistance
(2024-07-18) Mann, Gagandeep Singh; Adegoke, Olasunkanmi A. J.
Insulin resistance is the reduced responsiveness of a target tissue to insulin. Insulin resistance is an underlying cause of Type 2 diabetes mellitus (T2DM) and cardiovascular diseases, two debilitating diseases. Therefore, targeting insulin resistance can help prevent the development of T2DM and cardiovascular diseases. Dietary protein, and in particular branched-chain amino acids (BCAAs; leucine, valine and isoleucine) stimulate muscle protein synthesis, and regulate body weight and glucose homeostasis. However, despite these benefits, circulating levels of BCAAs and BCAA metabolites, branched-chain a-ketoacids (BCKAs) are upregulated in insulin-resistant states like T2DM. This raises the question if upregulated levels of BCAAs and BCKAs cause insulin resistance or are a symptom of insulin resistance. Numerous studies have also shown how insulin resistant states can regulate the BCAA catabolic pathway and the enzymes involved, and how targeting this pathway can provide benefits in regards to insulin resistance and its sequalae. Thus, the purpose of this dissertation is to examine the link between BCAAs and their metabolism, and insulin resistance. Previous in vitro studies have showed that depletion of branched-chain ketoacid dehydrogenase (BCKD), the enzyme responsible for the catabolism of BCKAs, suppressed insulin-stimulated glucose uptake in L6 myotubes and the metabolite of leucine, ketoisocaproic acid (KIC) worsens it. Thus, I demonstrated that interventions that increased BCKD activity improved insulin sensitivity and attenuated the suppressive effect of KIC on insulin sensitivity in L6 myotubes. We have previously shown that KIC reduces insulin-stimulated glucose transport in muscle cells. However, contributions from other tissues aside from skeletal muscle in BCAA metabolism emphasize the importance of studying the effect of KIC gavage in vivo as well. Whereas KIC alters insulin signaling in the liver, it did not affect whole-body insulin tolerance. Finally, since BCAA catabolism is implicated in many chronic conditions like insulin resistance, and age is a major risk factor in insulin resistance, we assessed how aging affects BCAA catabolism in both sexes. There was an increase in plasma BCAAs of old male mice, but changes in BCAA levels in plasma/tissues were not largely consistent with any changes in metabolic enzyme abundance/activity and did not correlate with changes in insulin sensitivity with sex or aging. Taken together, this thesis shows that although KIC suppresses glucose transport in vitro and its effect is attenuated by increasing BCAA oxidation, it does not affect insulin sensitivity in vivo likely due to contributions of the liver to catabolize KIC. Also, increases in plasma BCAAs seen in older male mice does not correlate with increased insulin resistance, suggesting that greater BCAAs in plasma may only be present in disease states. Together these studies suggest that altered BCAA levels do not cause insulin resistance but are a result of insulin resistance.
Open Access
USPORT Student Athletes’ Dietary Habits and the Impact of Various Barriers on Nutritional Intake and Health/Performance
(2024-07-18) Morassutti, Emerson Donneral; Macpherson, Alison
Introduction: Collegiate athletes face unique lifestyle circumstances compared to other athletic populations that can affect their daily nutrition habits. Purpose: To understand student-athletes (SAs) dietary habits and identify barriers faced by SAs that impact food intake. Methods: Cross-sectional study using an 89-question survey. Results: Thirty percent of SAs included in this study reported not consistently eating 3 meals per day and 46% reported being hungry before going to bed. Almost 75% of SAs reported that they were not able to access high quality food on campus and 80% reported that their daily schedule limited their ability to cook and prepare meals. More than half of SAs reported worrying about running out of food due to a lack of money. Conclusion: Lack of time, financial issues, and limited access to food on campus were prevalent barriers that affected nutritional intake
Open Access
The Effect of Age and Sex on Chemotherapy-Induced Cachexia and Branched-Chain Amino Acid Metabolism
(2024-07-18) Mora, Stephen; Adegoke, Olasunkanmi A. J.
Cachexia remains one of the most complex and challenging aspects in cancer care. The impact of cachexia on body wasting, particularly on the depletion of muscle mass, significantly impairs patient’s energy, strength and quality of life. Tumour-related factors and poor nutritional status are associated with cachexia development. Additionally, while effective in combatting cancer, chemotherapy causes appetite loss, fatigue, altered metabolism and decreased physical activity, all contributing to muscle tissue breakdown and cachexia. Decades of research into investigating interventions to mitigate the effects of cachexia have been unsuccessful. Even the use of nutritional supplements like the branched-chain amino acids (BCAA) in reversing cachexia remains limited and inconsistent. However, researchers typically prioritize tumour BCAA metabolism and overlook these amino acids in the skeletal muscle. In addition, studies investigating chemotherapy-induced cachexia frequently utilize young male animals and the effects of chemotherapy on the abundance and activity of enzymes involved in BCAA metabolism have not extensively been compared across the sexes, nor studied in aged animal tissues. Understanding the alterations in skeletal muscle BCAA metabolism and availability following chemotherapy, especially across different sex and age groups, may help provide a better understanding of why certain interventions are ineffective in treating cachexia and may present findings that more accurately represent clinical diversity. Therefore, the objective of this dissertation is to examine the effect of age and sex on the mechanisms and severity of chemotherapy-induced cachexia, with a focus on BCAA availability, metabolism and transporter expression in young and aged animals. Briefly, I showed that preventing the degradation of LAT1, a transporter protein crucial for BCAA uptake into skeletal muscle, counteracted the effects of chemotherapy-induced damage on myotubes. Further, in-vivo, I showed sex-dependent differences in the susceptibility of young and aged animals to chemotherapy-induced cachexia. I also show that altered BCAA availability and metabolism following chemotherapy may contribute to muscle wasting in a sex and age-dependent manner. Findings from this dissertation suggest that interventions regulating muscle amino acid transporters may represent a promising strategy to treat cachexia. These findings underscore the need for age- and sex-specific responses when developing interventions that can manage cachexia.
Open Access
Regulation of Substrate Metabolism and Renin-Angiotensin System with Dietary and Pharmacological Interventions: Implications for Obesity and Related Disorders
(2024-07-18) Da Eira, Daniel Pereira; Ceddia, Rolando
This dissertation investigates the effects of the ketogenic diet (KD) on adipose tissue (AT) metabolism and renin-angiotensin system (RAS) function and potential implications for other tissues, including lung, heart and skeletal muscle. In the first study, it was demonstrated that despite increasing fat mass, a KD enhanced energy-dissipating mechanisms in white AT (WAT) and brown AT (BAT) by upregulating the machinery for triacylglycerol recycling in white adipocytes and uncoupled fatty acid (FA) oxidation and UCP1 protein levels in the BAT. These effects could potentially be attributed to the shift to the counterregulatory RAS arm in WAT observed in study 2, which has been shown to produce beneficial metabolic effects. In study 3, the effect of the KD on RAS components was investigated in the context of the lung and heart, where an obesity-induced elevation in pulmonary inflammation could underlie an increase in angiotensin converting enzyme 2 (ACE2), the receptor for SARS-CoV-2 cellular infection. We observed that the obesogenic, high-fat sucrose-enriched (HFS) diet elevated the pulmonary content of this receptor, whereas the KD did not alter ACE2 levels. Moreover, the KD significantly suppressed inflammation, relative to the HFS group, in the lung. Because AT releases energy substrate for utilization in peripheral tissues, the KD also affects substrate preference and metabolism in skeletal muscle. To our knowledge, little has been done with respect the metabolic effects of a KD on muscles with distinct fiber-type compositions. Therefore, we assessed the effects of the KD on glucose, fat, and ketone metabolism in skeletal muscles. We observed that the KD increased fat oxidation and ketolytic capacity, when compared to the HFS group, in a fiber-type specific manner. However, irrespective of oxidative capacity, the KD preserved insulin-stimulated glucose metabolism, whereas the HFS diet suppressed this parameter. In our final study, we used a pharmacological intervention (the adiponectin mimetic ALY688) to alter AT glucose and fat metabolism. Despite not altering glucose uptake in Epid or Sc Ing adipocytes, ALY688 significantly enhanced glucose oxidation. Together, these projects explore dietary and pharmacological interventions that alter the metabolic and endocrine roles of AT and investigate non-adipose tissues under KD conditions.
Open Access
Regulating Inflammation Through Exercise-Mediated Trained Immunity or Genetic Manipulation of the Interferon Locus
(2024-07-18) Murugathasan, Mayoorey; Abdul-Sater, Ali
Abstract Inflammation is a protective early immune response to infection or injury. A balanced inflammatory response, which is self-limiting and self-resolving, is essential to restore homeostasis. However, dysregulated inflammation is underlying many chronic diseases and infections. Strategies for balancing inflammation can be achieved in two ways 1) by inducing adaptations in immune cells through environmental/lifestyle factors such as exercise and 2) by genetically manipulating or pharmaceutically targeting key immune modulatory factors, such as interferons. In my thesis, I employed both approaches. First, we explored whether exercise training could induce adaptations in bone marrow-derived macrophages, resulting in trained immunity, known to occur in immune cells due to persistent metabolic and epigenetic changes. Data from this study suggest that chronic moderate exercise can influence the inflammatory responses of macrophages by reprogramming their metabolic and epigenetic landscape. Second, we evaluated the role of specific type I interferons (IFN-α and IFN-β), cytokines known for their antiviral and immunomodulatory functions, in virus infection and PAMPs (pathogen-associated molecular patterns) mediated inflammatory responses. To study this, we generated unique knockout (KO) mice of type I interferons (IFN-Is) locus and evaluated viral clearance and other parameters such as cytokine, interferon stimulated genes (ISG) signatures, and bone marrow hematopoiesis. Data from this study showed the importance of IFN-αs in early viral clearance and other parameters that measured antiviral and inflammatory responses, which encourages the need to study the individual IFN-Is in isolation using reliable mouse models to uncover their specific roles and targets. Overall, data from both approaches contributed significantly to improving our understanding of the mechanisms behind exercise and IFN-I mediated regulation of inflammatory responses.
Open Access
Exploration of the Mitochondria as a Potential Therapeutic Target in Duchenne Muscular Dystrophy
(2024-07-18) Bellissimo, Catherine Anne; Perry, Christopher G. R.
Duchenne muscular dystrophy (DMD) is a fatal muscle wasting condition resulting from the loss of the structural protein dystrophin. The disease is characterized by severe muscle wasting and weakness that results in early death due to cardiac and/or respiratory failure. Currently, there is no cure for DMD and current standard of care (glucocorticoid steroids) only addresses secondary pathologies, and is accompanied with a myriad of negative side effects. Previous work has established the mitochondria as a contributor to dystrophic pathology and a valid therapeutic target. The primary focus of this thesis was to examine novel therapies that modulate metabolism in DMD, to determine if secondary pathologies, including fibrosis, atrophy, weakness and mitochondrial stress are attenuated. Additionally, we aimed consider the effects of adenylates and creatine metabolism on mitochondrial permeability transition (mtPT) in a permeabilized muscle fibre system. Our study findings reveal that ATP significantly attenuates mtPT and that both creatine and ADP should be considered in buffer composition for assessment of mtPT. Next, using the mitochondrial-enhancing compound, Olesoxime, we examined the effect of attenuating mitochondrial stress on dystrophic pathology. Unexpectedly, improvements to mitochondrial respiration and reactive oxygen species attenuation, were creatine-dependent, indicating that creatine sensitivity was preserved by Olesoxime treatment. These improvements to bioenergetics also happened in association with markers of muscle breakdown (serum creatine kinase), and improvement in muscle function (cage hand time and recovery of diaphragm force after fatigue). Finally, short-term treatment with the novel adiponectin receptor agonist, ALY688-SR, mitigated aspects of mitochondrial stress in quadriceps, diaphragm and hippocampus, while improving markers of fibrosis and muscle atrophy in the diaphragm, and recognition memory. Overall, this thesis indicates that attenuating mitochondrial stress in dystrophic muscle and brain improves markers of muscle function and quality, while preserving cognitive function and warrants longer term treatment protocols.