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Full Text, Thesis (PhD Doctorate), Doctor of Philosophy (PhD), School Allied Health Sciences, Griffith Health, Regular physical activity, or exercise, is beneficial in the maintenance of health and wellbeing of the human body. With respect to the cardiovascular system, the potential benefits of physical activity in the prevention, reduction of frequency and severity, and enhanced rehabilitation, of heart disease are clear. However, many questions remain regarding factors such as the mode, duration, and intensity of physical activity and the cardiac impacts of these variables. Moreover, underlying mechanisms remain to be detailed. The current narrative from health organisations and governments worldwide has been the mantra of ‘exercise is medicine’, with a two-pronged approach: to enable the population to meet the minimum standards of daily physical activity, and to limit the amount of extended sedentariness. What is clear is that very few meet these standards, and heart disease, along with other associated chronic diseases attributed to a lack of activity and suboptimal diet, remain top of the list for all-cause mortality and morbidity. The issues pertaining to this problem are as broad as the benefits of exercise itself, and they include behavioral and societal issues beyond the scope of this thesis. The experiments in this thesis aim to specifically investigate the molecular underpinnings of the cardiac and systemic changes that occur in the exercised body. With this knowledge, it is possible to proceed further with potential solutions, such as: personalised exercise protocols for a specific health outcome, determination of short-term, long-term, and lifelong effects of activity or inactivity, and development of agents that may mimic or promote some of the benefits of exercise, especially for those unable to undertake physical exertion. The first experimental studies in this thesis investigated whether short-term voluntary wheelrunning in 8-week old mice beneficially modulates myocardial ischemic tolerance, signaling kinases, and gene expression patterns (Chapter 3). Trans

It remains incompletely understood whether there is an association between the transcriptome profiles of skeletal muscle and blood leukocytes in response to exercise or other physiological stressors. We have previously analyzed the changes in the muscle and blood neutrophil transcriptome in eight trained men before and 3 h, 48 h and 96 h after 2 h cycling and running. Because we collected muscle and blood in the same individuals and under the same conditions, we were able to directly compare gene expression between the muscle and blood neutrophils. Applying weighted gene co-expression network analysis (WGCNA) as an advanced network-driven method to these original datasets enabled us to compare the muscle and neutrophil transcriptomes in a rigorous and systematic manner. Two gene networks were identified that were preserved between skeletal muscle and blood neutrophils, functionally related to mitochondria and post-translational processes. Strong preservation measures (Zsummary > 10) for both muscle-neutrophil gene networks were evident within the post-exercise recovery period. Muscle and neutrophil gene co-expression was strongly correlated in the mitochondria-related network (r = 0.97; p = 3.17E-2). We also identified multiple correlations between muscular gene sub-networks and exercise-induced changes in blood leukocyte counts, inflammation and muscle damage markers. These data reveal previously unidentified gene co-expression between skeletal muscle and blood neutrophils following exercise, showing the value of WGCNA to understand exercise physiology. Furthermore, these findings provide preliminary evidence in support of the notion that blood neutrophil gene networks may potentially help us to track physiological and pathophysiological changes in the muscle.

Copyright © 2017 the American Physiological Society. It remains incompletely understood whether there is an association between the transcriptome profiles of skeletal muscle and blood leukocytes in response to exercise or other physiological stressors. We have previously analyzed the changes in the muscle and blood neutrophil transcriptome in eight trained men before and 3, 48, and 96 h after 2 h cycling and running. Because we collected muscle and blood in the same individuals and under the same conditions, we were able to directly compare gene expression between the muscle and blood neutrophils. Applying weighted gene coexpression network analysis (WGCNA) as an advanced network-driven method to these original data sets enabled us to compare the muscle and neutrophil transcriptomes in a rigorous and systematic manner. Two gene networks were identified th at were preserved between skeletal muscle and blood neutrophils, functionally related to mitochondria and posttranslational processes. Strong preservation measures (Z summary > 10) for both muscle-neutrophil gene networks were evident within the postexercise recovery period. Muscle and neutrophil gene coexpression was strongly correlated in the mitochondria-related network (r = 0.97; P = 3.17E-2). We also identified multiple correlations between muscular gene subnetworks and exercise-induced changes in blood leukocyte counts, inflammation, and muscle damage markers. These data reveal previously unidentified gene coexpression between skeletal muscle and blood neutrophils following exercise, showing the value of WGCNA to understand exercise physiology. Furthermore, these findings provide preliminary evidence in support of the notion that blood neutrophil gene networks may potentially help us to track physiological and pathophysiological changes in the muscle.

© The Author 2017. Aims Strenuous endurance exercise acutely increases myocardial wall stress and evokes transient functional cardiac perturbations. However, it is unclear whether exercise-induced functional cardiac disturbances are ubiquitous throughout the myocardium or are segment specific. The aim of this study was to examine the influence of high-intensity endurance exercise on global and segmental left (LV) and right (RV) ventricular tissue deformation (strain). Methods and results Echocardiography was used to measure strain in 23 active men (age: 28±2 years; VO 2 peak : 4.5±0.7 L min -1 ) at rest and during a standardized low-intensity exercise challenge, before and after a 90-min high-intensity endurance cycling intervention. Following the cycling intervention, LV and RV global strain decreased at rest (LV: -18.4±0.4% vs.-17.7±0.4%, P < 0.05; RV:-27.6±0.7% vs.-26.4±0.6%, P < 0.05) and by a greater extent during the lowintensity exercise challenge (LV: -21.3±0.4% vs. -19.2±0.5%, P < 0.01; RV: -28.4±0.8% vs.-23.5±0.9%, P < 0.01). Reductions in LV strain were unique to regions of RV attachment (e.g. LV septum: -24.4±0.5% vs.-21.4±0.6%, P < 0.01) with lateral (218.9±0.4% vs. 218.4±0.5%) and posterior segments (-19.5±0.4% vs.-18.8±0.7%) unaffected. Similarly, augmentation of strain from rest to exercise was abolished in the RV free wall (-1.1±1.0% vs. 2.9±1.2%, P < 0.01), reduced in the septum (-4.6±0.4% vs. -2.4±0.5%, P < 0.01), and unchanged in the lateral (-1.2±0.6% vs. -0.9±0.6%) and posterior walls (-1.7±0.6% vs. -1.3±0.7%). Conclusion Changes in ventricular strain following high-intensity exercise are more profound in the right ventricle than in the left ventricle. Reductions in LV strain were unique to the septal myocardium and may reflect ventricular interactions secondary to exercise-induced RV dysfunction.

Full Text, Thesis (PhD Doctorate), Doctor of Philosophy (PhD), School of Allied Health, Griffith Health, Endurance exercise training stimulates numerous adaptive changes to the structure, morphology and function of the human heart. Recent evidence suggests that a prolonged and strenuous bout of exercise, such as an ultra-endurance marathon or triathlon event, may results in temporary autonomic, biochemical and functional abnormalities which predominantly arise in the right ventricle. The impact of routine day-to-day endurance exercise training on exercise-induced cardiac disturbances is less clear, but likely influenced by hemodynamic, hormonal and metabolic factors that are related to the exercise intensity and duration. This thesis aimed to determine the time-course development (throughout exercise and during recovery) of cardiac perturbations evoked by exercise bouts that are typical of day-to-day endurance training. Indices of cardiac electrical conduction (atrial and ventricular conduction dynamics), autonomic activity (heart rate variability), ventricular mechanical function (left and right ventricular strain), and biomarkers of cardiac injury (serum cTn T & I) were examined in a cohort of recreationally active and trained men. The assessment of ventricular mechanical function during exercise is a key element of this thesis that enabled the exploration of functional cardiac limitations throughout and following endurance exercise. To determine the magnitude and time-course of exercise-induced functional and biochemical cardiac perturbations a laboratory based study was used to manipulate exercise intensity and duration while holding total mechanical work constant.

© 2016 The Physiological Society. Strenuous endurance exercise induces transient cardiac perturbations with ambiguous health outcomes. The present study investigated the magnitude and time-course of exercise-induced functional and biochemical cardiac perturbations by manipulating the exercise intensity-duration matrix. Echocardiograph-derived left (LV) and right (RV) ventr icular global longitudinal strain (GLS), and serum high-sensitivity cardiac troponin (hs-cTnI) concentration, were examined in 10 males (age: 27 ± 4 years; V?O2, peak : 4.0 ± 0.8 l min -1 ) before, throughout (50%, 75% and 100%), and during recovery (1, 3, 6 and 24 h) from two exercise trials. The two exercise trials consisted of 90 and 120 min of heavy- and moderate-intensity cycling, respectively, with total mechanical work matched. LVGLS decreased (P < 0.01) during the 90 min trial only, with reductions peaking at 1 h post (pre: -19.9 ± 0.6%; 1 h post: -18.5 ± 0.7%) and persisting for > 24 h into recovery. RVGLS decreased (P < 0.05) during both exercise trials with reductions in the 90 min trial peaking at 1 h post (pre: -27.5 ± 0.7%; 1 h post: -25.1 ± 0.8%) and persisting for > 24 h into recovery. Serum hs-cTnI increased (P < 0.01) during both exercise trials, with concentrations peaking at 3 h post but only exceeding cardio-healthy reference limits (14 ng l -1 ) in the 90 min trial (pre: 4.2 ± 2.4 ng l -1 ; 3 h post: 25.1 ± 7.9 ng l -1 ). Exercise-induced reductions in ventricular strain and increases in cardiac injury markers persist for 24 h following exercise that is typical of day-to-day endurance exercise training; however, the magnitude and time-course of this response can be altered by manipulating the intensity-duration matrix. Key points: Strenuous endurance exercise induces transient functional and biochemical cardiac perturbations that persist for 24-48 h. The magnitude and time-course of exercise-induced reductions in ventricular function and increases in cardiac in

© 2015, Wiley Periodicals, Inc. Left ventricular (LV) twist mechanics are routinely assessed via echocardiography in clinical and research trials investigating the function of obliquely oriented myocardial fibers. However, echocardiograph-derived measures of LV twist may be compromised by nonstandardized acquisition of the apical image. This study examined the reproducibility of echocardiograph-derived parameters of apical twist mechanics at multiple levels of the apical myocardium. Two sets of 2D LV parasternal short-axis images were obtained in 30 healthy subjects (24 men; 19-57 year) via echocardiography. Images were acquired immediately distal to the papillary muscles (apical image 1), immediately above the point of LV cavity obliteration at end systole (apical image 3), and midway between apical image 1 and apical image 3 (apical image 2). Repeat scans were performed within 1 hour, and twist mechanics (rotation and rotation rate) were calculated via frame-by-frame tracking of natural acoustic echocardiographic markers (speckle tracking). The magnitude of apical rotation increased progressively toward the apex (apical image 1: 4.2 ± 2.1, apical image 2: 7.2 ± 3.9, apical image 3: 11.8 ± 4.6). apical images 1, 2, and 3 each had moderate to good correlations between repeat scans (ICC: 0.531-0.856). When apical images 1, 2, and 3 were averaged, rotation was 7.7 ± 2.7 and between-scan correlation was excellent (ICC: 0.910). Similar results were observed for systolic and diastolic rotation rates. Averaging multiple standardized apical images, tending progressively toward the apex, generated the most reproducible rotation indices and may be optimal for the assessment of LV twist mechanics across therapeutic, interventional, and research studies; however, care should be taken given the influence of acquisition level on the magnitude of apical rotation.

© 2016 - IOS Press and the authors. All rights reserved. BACKGROUND: The purpose of the present study was to investigate the effects of regular treadmill walking on plasma factors that increase low-shear blood viscosity and red blood cell aggregation in older women with type 2 diabetes. METHODS: Eighteen women with type 2 diabetes (age: 69±3 yr; body mass index: 30.5±5.0 kg·m -2 ) performed 12-wk of 120 min·wk -1 of supervised treadmill walking at an intensity equivalent to the gas-exchange threshold. Peak exercise values, anthropometry and blood indices of diabetic status, markers of inflammation, and plasma fibrinogen were analysed during a 6-wk pre-training 'control' period, and then after 6 and 12-wk of regular walking. RESULTS: Regular walking significantly increased peak oxygen uptake (p = 0.01). Body mass, waist to hip ratio, and glycaemic control did not change. Systolic and diastolic blood pressures decreased by 8.5 (p < 0.01) and 7.2 (p < 0.01) respectively, cholesterol to high-density lipoprotein (HDL) ratio decreased by 9.6 (p = 0.01), and HDL concentration significantly increased (p = 0.01). While 12 wk of regular walking did not significantly alter plasma concentrations of interleukin-6 (IL-6), tumour necrosis factor-a, or C-reactive protein, plasma fibrinogen concentration decreased by 6.9 (p < 0.01) and plasma interleukin-10 (IL-10) concentration increased from 1.15±0.32 to 1.62±0.22 mmol·L -1 (p < 0.04). CONCLUSIONS: Improved plasma inflammatory profile and decreased plasma fibrinogen concentration is induced by regular walking, independent of glycaemic control. These factors may mediate the improved haemorheology associated with exercise training in metabolic disorders.