Dissertations / Theses on the topic 'Physiological hypertrophy'

Cardiac hypertrophy defines an adaptive process brought about in response to sustained increases in haemodynamic work. Cardiomyocytes undergo an initial compensatory phase in which enlargement and contractility alterations normalise wall stress and maintain adequate perfusion of organs. In pathological hypertrophy, this deteriorates to a decompensated state characterised by ventricular dysfunction and predisposition to heart failure. In contrast, physiological hypertrophy and associated enhanced cardiac functioning arising from chronic exercise training does not progress to heart failure. Determination of the molecular pathways underlying myocardial hypertrophy remains a challenge for cardiovascular research. The objective of the work presented in this thesis was to identify genes differentially expressed during pathological and physiological hypertrophy in order to enhance our knowledge of the mechanistic processes involved. A reverse Northern hybridisation method was applied to profile the expression of specifically selected genes in the hypertrophic models examined. Functional categories represented in the gene panel assembled included cardiac contractile and cytoskeletal markers, matrix metalloproteinases, vasoactive pathway factors, calcium handling genes, ion channels, cardiac regulatory factors, signalling pathway intermediates, apoptotic factors and histone deacetylases. In order to investigate pathological hypertrophy, a deoxycorticosterone acetate-salt (DOCA-salt) rat model was utilised. DOCA-salt treated rats used in this study demonstrated a 1.4-fold increase in heart weight to body weight ratio compared to controls. Impaired cardiac function indicative of a decompensated pathological phenotype in the DOCA-salt treated group was demonstrated by way of decreased chamber size, impaired myocardial compliance and significantly reduced cardiac output. Reverse Northern hybridisation analysis of 95 selected genes identified a number of candidates with differential expression in hearts of DOCA-salt treated rats. Increased gene expression was demonstrated for the collagenase MMP1 and stress-activated signal transduction factor Sin1. In contrast, the sarcoplasmic reticulum calcium ATPase SERCA-2 and anti-apoptotic factor BCL2l-10 genes exhibited decreased expression. To investigate changes in gene expression associated with physiological hypertrophy, use was made of an endurance run-trained rat model. The run-trained rats used in this study demonstrated a 24.1% increase in heart weight to body weight ratio and improvements in performance consistent with physiological cardiac adaptation. These performance indicators included improvements in systolic volume, cardiac output, myocardial compliance and bio-energetic function. Reverse Northern hybridisation expression analysis of 56 genes identified a number of differentially expressed mRNA transcripts in run-trained hypertrophied hearts. Four genes shown to demonstrate reduced expression in the run-trained rat model were interleukin-1 receptor associated kinase (IRAK1) and the developmentally expressed transcription factors Nkx-2.3, dHAND, and IRX-2. Based upon the reverse Northern hybridisation results, four genes were selected for Western blotting analysis of rat cardiac tissue. Of these, MMP1 and a putative isoform of Sin1 exhibited increased levels in DOCA-salt treated hypertrophic left ventricular tissue, results that correlate with the findings of increased mRNA expression for these two genes. Therefore, this study identified MMP1 and Sin1 as candidates involved in pathological but not physiological hypertrophy. This finding is in accord with other recent investigations demonstrating that pathological hypertrophy and physiological hypertrophy are associated with distinct molecular phenotypes. An aside to the major objective of identifying genes differentially regulated in left ventricular hypertrophy involved the application of the P19CL6 cell in vitro model of cardiomyogenesis to compare protein expression during hypertrophy and development. The Sin1 isoform, found to be up-regulated during DOCA-salt induced hypertrophy, was also shown to be more abundant in differentiating, than non-differentiating, P19CL6 cells. This result is consistent with the developing paradigm that implicates 'fetal' genes in the hypertrophic remodelling process.

Cardiac hypertrophy defines an adaptive process brought about in response to sustained increases in haemodynamic work. Cardiomyocytes undergo an initial compensatory phase in which enlargement and contractility alterations normalise wall stress and maintain adequate perfusion of organs. In pathological hypertrophy, this deteriorates to a decompensated state characterised by ventricular dysfunction and predisposition to heart failure. In contrast, physiological hypertrophy and associated enhanced cardiac functioning arising from chronic exercise training does not progress to heart failure. Determination of the molecular pathways underlying myocardial hypertrophy remains a challenge for cardiovascular research. The objective of the work presented in this thesis was to identify genes differentially expressed during pathological and physiological hypertrophy in order to enhance our knowledge of the mechanistic processes involved. A reverse Northern hybridisation method was applied to profile the expression of specifically selected genes in the hypertrophic models examined. Functional categories represented in the gene panel assembled included cardiac contractile and cytoskeletal markers, matrix metalloproteinases, vasoactive pathway factors, calcium handling genes, ion channels, cardiac regulatory factors, signalling pathway intermediates, apoptotic factors and histone deacetylases. In order to investigate pathological hypertrophy, a deoxycorticosterone acetate-salt (DOCA-salt) rat model was utilised. DOCA-salt treated rats used in this study demonstrated a 1.4-fold increase in heart weight to body weight ratio compared to controls. Impaired cardiac function indicative of a decompensated pathological phenotype in the DOCA-salt treated group was demonstrated by way of decreased chamber size, impaired myocardial compliance and significantly reduced cardiac output. Reverse Northern hybridisation analysis of 95 selected genes identified a number of candidates with differential expression in hearts of DOCA-salt treated rats. Increased gene expression was demonstrated for the collagenase MMP1 and stress-activated signal transduction factor Sin1. In contrast, the sarcoplasmic reticulum calcium ATPase SERCA-2 and anti-apoptotic factor BCL2l-10 genes exhibited decreased expression. To investigate changes in gene expression associated with physiological hypertrophy, use was made of an endurance run-trained rat model. The run-trained rats used in this study demonstrated a 24.1% increase in heart weight to body weight ratio and improvements in performance consistent with physiological cardiac adaptation. These performance indicators included improvements in systolic volume, cardiac output, myocardial compliance and bio-energetic function. Reverse Northern hybridisation expression analysis of 56 genes identified a number of differentially expressed mRNA transcripts in run-trained hypertrophied hearts. Four genes shown to demonstrate reduced expression in the run-trained rat model were interleukin-1 receptor associated kinase (IRAK1) and the developmentally expressed transcription factors Nkx-2.3, dHAND, and IRX-2. Based upon the reverse Northern hybridisation results, four genes were selected for Western blotting analysis of rat cardiac tissue. Of these, MMP1 and a putative isoform of Sin1 exhibited increased levels in DOCA-salt treated hypertrophic left ventricular tissue, results that correlate with the findings of increased mRNA expression for these two genes. Therefore, this study identified MMP1 and Sin1 as candidates involved in pathological but not physiological hypertrophy. This finding is in accord with other recent investigations demonstrating that pathological hypertrophy and physiological hypertrophy are associated with distinct molecular phenotypes. An aside to the major objective of identifying genes differentially regulated in left ventricular hypertrophy involved the application of the P19CL6 cell in vitro model of cardiomyogenesis to compare protein expression during hypertrophy and development. The Sin1 isoform, found to be up-regulated during DOCA-salt induced hypertrophy, was also shown to be more abundant in differentiating, than non-differentiating, P19CL6 cells. This result is consistent with the developing paradigm that implicates 'fetal' genes in the hypertrophic remodelling process.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Biomedical Sciences
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Abstract :Cardiac hypertrophy has been identified as the most important independent risk factor for cardiovascular-related morbidity and mortality and is therefore regarded as a pathological condition. Despite this, beneficial physiological forms also appear to exist, such as in response to exercise, leading to maintained or improved cardiac function. The aim of this thesis was to examine two distinct rodent models, an endurance run-trained rat, and the DOCA-salt hypertensive rat, representing physiological and pathological hypertrophy, respectively, in order to develop a better understanding of the molecular changes associated with each condition. The thesis also examined the effect of dietary supplementation of L-arginine to the pathological model, a treatment that has been shown to ameliorate/prevent many of the cardiovascular impairments. Studies examined selected candidate genes (qRT-PCR), including conventional biomarkers of hypertrophy and exploratory analysis of adenosine-related genes (given adenosine’s established regulatory and protective role in the heart, yet minimally studied in cardiac hypertrophy), and explored global transcriptomic shifts via microarrays. The hypothesis of this work was that cardiac hypertrophy lies on a continuum, with similarities existing at the cardiac transcriptional level between early (adaptive) stages of pathological hypertrophy (DOCA-salt rat) and later stages of physiological hypertrophy (endurance run-trained rat). Examination of ten biomarkers of hypertrophy (ANF, BNP, -MHC, -MHC, cardiac -actin, skeletal -actin, SERCA2, PPAR, Coll I and III) revealed that the pathological model displayed alterations in the expression of many of these molecules in line with the literature. These changes were not observed in the physiological model. This therefore reinforces the value of conventional biomarkers in delineating pathological vs. physiological hypertrophies, and reveals fundamental differences in genesis of these two forms of hypertrophy. The adenosine system (receptors and purine handling molecules) was altered in the pathological hypertrophy model as evidenced by the modulation of genes corresponding to A3AR, Ada, and Adk, with a potential shift from purine salvage towards degradation of adenosine to inosine. Furthermore, this study represents the first report of altered regulation of the nucleoside transporter ENT3 in a pathological condition. None of these changes were seen in the physiological model with only modulation of the A2aAR evident. Examination of the transcriptional response to physiological hypertrophy revealed that short (6 week) and long (12 week) training programmes resulted in different profiles, likely reflecting progression of the hypertrophy process. The short programme stimulated genes associated with the mitochondria, oxidoreductase, receptor binding and coenzymemetabolismand repressed the expression of transcripts associated with phosphorylation, catalytic activity, defence/immunity and energy pathways. Thus, initial changes observed are primarily of a metabolic and signalling nature. In contrast, the longer programme resulted in shifts in protein handling and synthesis, and genes involved in structural molecule activity, nucleotide binding and cellular homeostasis. These patterns support a progression with time from initial metabolic adaptations to longer term shifts in protein phenotype and structural adaptations, consistent with longer term changes in heart structure. Similarly, the pathologicalmodel displayed different time-dependent gene expression profiles. Overall, the pattern of changewith early (2week) treatment is suggestive of changes in intracellular signalling and increasing transcriptional capacity with the later changes (at 4 weeks) indicative of structural adaptations (intra- and extracellularly) togetherwith an inflammation response. Genes coding for calciumhandling, ion channels, and gap junctions were altered throughout themodel andmay contribute to electrical conduction defects and cardiac dysfunction. The adrenergic signalling pathway was modulated as associated signalling molecules were down-regulated. The study revealed many expected and novel changes, of which further study should focus on: calcium regulation, metabolic regulation, gap junctions, and (as might be exii pected) signalling via the adrenergic pathway, insulin-like growth factor, PI3K, and Jak/STAT. L-Arginine modulated biomarker expression in pathological hypertrophy, with stimulation of PPAR and SERCA2 with little or no effect on the adenosine-related genes. L-Arginine affected the overall transcriptional response to DOCA-salt treatment, stimulating genes involved in cell growth andmaintenance, nerve transmission, heparin and glycosaminoglycan binding, peptide binding and protein targeting, as well as the repression of genes related to apoptosis (favouring a pro-apoptotic state), intracellular organisation and biogenesis, and enzyme inhibitor activity. The beneficial effects of L-arginine in the setting of pathological hypertrophy may be due to modulation of metabolism, improving calcium handling and overall enhancing cellular functioning. This work demonstrates that cardiac hypertrophy is clearly different at the transcriptional level depending upon the aetiology. This repudiated the hypothesis of the thesis that cardiac hypertrophy lies on a continuum with similarities existing at the cardiac transcriptional level between early (adaptive) stages of pathological hypertrophy and later stages of physiological hypertrophy. Whilst some of the data was in accordance with current knowledge of these states, novel changes were also discovered, contributing to our understanding of the molecular aspects of cardiac hypertrophy.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
Griffith University. School of Medical Science.
Griffith Health
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Introduction: The aims of the current investigations were to modulate muscle-tendon complex (MTC - vastus lateralis [VL] & patella tendon [PT]) adaptations through mechanical stress and strain. Groups performed resistance training (8 weeks) with the MTC placed in a shortened (SL) or a lengthened position (LL) with internal loading standardised. A third group trained over an entire ROM (LX) with the external loading matched to that in SL. MTC response to detraining (4 weeks) was also measured. A control, untrained group was measured during this 12-week period. Methods: Measurements using ultrasonography, dynamometry, electromyography and dual energy absorptiometry were made at baseline (week 0), post-training (week 8), detraining 1 (week 10) and detaining 2 (week 12). VL measurements included volume, cross-sectional area (CSA), and architecture. PT properties included stiffness and Young’s Modulus. Quadriceps MTC function was measured by isometric maximal voluntary contractions (MVC) over a range of joint –angles. Circulating levels of a growth factor (IGF-I) and cytokines (TGF-β1, TNF-α) were measured using enzyme-linked immuno-sorbant assay. Main Results: VL volume, CSA, fascicle length, PT stiffness, modulus, quadriceps MVCs and IGF-I (LL only) were significantly greater (p<0.05) in both LL and LX groups compared to SL post-training. During detraining, CSA, fascicle length, stiffness, modulus, IGF-I (LL only) remained significantly elevated in the LL and LX groups compared to SL. There was no significant change in the control group in any measurement during the study period (p>0.05). Conclusion: Training with the MTC in a lengthened position is more effective for inducing (and retaining) enhanced training MTC adaptations, owing to internal mechanical and physiological stress in this position. This loading method should therefore be incorporated into a structured resistance training program for a range of populations such as athletic, recreationally active, clinical or elderly individuals.

Sub-endocardial fibres line the inner surface of both ventricles and are responsible for longitudinal oscillations of the mitral annulus, such oscillations may be measured using tissue Doppler echocardiography (IDE). During systole the annulus descends and during early diastole (ETDE) and atrial systole (ATDE) itascends. This thesis examined whether changes in the velocity of the annulus ineach of these phases of oscillation, measured using tissue Dopplerechocardiography (TDE), could determine the nature of increases in left ventricular size (pathological or physiological). Study one examined differences at rest in longitudinal velocities between individuals with hypertrophic cardiomyopathy (HCM), hypertension (HT), weightlifters, runners and controls, (n = 15 all groups) and all groups were aged between 20 - 36 years. The results demonstrated that both pathological groups had systolic and ETDE velocities significantly lower than groups with physiological hypertrophy (weightlifters or runners) or controls p < 0.05. AIDE however was not significantly different between groups. Additionally runners also demonstrated a significantly higher ETDE than either weightlifters or controls (p < 0.05). Binomial logistic regression identified longitudinal systolic velocity < 9 cm s" 1 and ETDE velocity < 11 cm s" 1 as the best combination of variables to predict pathological increases in heart size. Study two examined older subjects in order to determine whether the criteria set out in study one were applicable to senior athletes. The subject groups were the same as in study one however all subjects were aged between 36-55. In this case systolic annular velocity was significantly lower in groups with pathological LVH but ETDE < 9 cm s" 1 was a better differentiator. Binomial logistic regression identified ETDE < 9 cm s" 1 and a mitral E / A ratio < 1 as the best combination of variables to predict pathological LVH. Study three examined the age related changes in long axis function using the pooled data from studies one and two. This demonstrated that in the pathological LVH groups only ETDE / ATDE ratio was significantly correlated with age (r = - 0.5 p < 0.05) suggesting that there appears to be no summation of the effects of pathology and age on mitral annular velocities. The control groups demonstrated a significant age related reduction in all long axis variables (systolic velocity r = - 0.7 p < 0.05; ETDE r = - 0.6 p < 0.01; ATDE r = 0.5 p < 0.05; ETD E / ATDE r = - 0.5 p< 0.01). Weightlifters however did not demonstrate an age related decline in either systolic or diastolic annular velocities. Runners had no age related decline in systolic annular velocities, and whilst they had an age dependent fall in ETDE ( r = - 0.62 p < 0.05) the older runners ETDE were still significantly faster (p < 0.05) than that seen in control subjects. Study four investigated relationship between mitral annular velocity and VOiruK in runners, weightlifters and controls. These results demonstrated peak exercise E TDE strongly correlated to VO^PEAK (r = 0.8 p < 0.01). ConclusionsTaken together these data suggest that longitudinal velocities of the mitral annulus may be useful in determining the nature of increases in heart size, in addition the increased performance of endurance - trained athletes is due in part to functional changes of the long axis.

The purpose of the present study was to examine the relationship between exercise induced muscle damage and growth factors during two different modes of exercise. Nine healthy untrained male subjects participated in this study and performed two separate single bouts of isokinetic concentric (Con) and eccentric (Ecc) leg extension exercise on the CYBEX NORMT°". The workload was maintained at 75% of 1 RM for each trial, respectively. The maximum sets of 10 repetitions were performed during the Con trial, and the number was also duplicated during the Ecc trial, with 40 seconds of rest between sets. Serum levels of hGH, creatine kinase (CK), and lactic acid were measured, and the CK level was used to determine the degree of muscle tissue damage. A muscle soreness questionnaire was provided to the subjects to assess the degree of quadriceps muscle soreness following each trial. The EMG activity of the rectus femoris and vastus medialis muscles was recorded during each trial. The results of the present study demonstrated no significant differences in hGH output and CK activity between the exercise trials, although there was a significant different lactic acid response (P < 0.05). However, the Con trial produced significant increases (P < 0.05) in hGH and CK levels above the resting value at the post-exercise times. In fact, the 75% Con trial conducted in this study induced an increase in hGH release (peak: 8.23 ± 3.21 ng/ml) that was 2 X higher than a 120% Ecc trial (peak: 3.8 ± 1.2 ng/mI) of the prior study. The results of the present study demonstrate that a single bout of Con resistance exercise at the same intensity (75% of 1 RM), angular velocity, and ROM as a single bout of Ecc exercise can produce greater increases in hGH output and CK response than its Ecc counterpart. This finding does not support the previous results from this laboratory, showing that Ecc exercise is a stronger promoter of hGH output. However, it suggests that the amount of work performed is an important factor for hGH release because the exercise volume applied in the present study was greater than that of the prior study. The CK response of the subjects in this study, as well as the previous work indicate that hGH output is also dependent on exercise that elicits muscle damage. Therefore, the results of the present study suggest that the mode of exercise, Con vs. Ecc, is not as important as the stress placed on the exercising muscle in order to induce optimal muscle hypertrophy.
School of Physical Education

Skeletal muscle possesses remarkable plasticity in responses to altered mechanical load. An established murine model used to increase mechanical load on a muscle is the surgical removal of the gastrocnemius and soleus muscles, thereby placing a functional overload on the plantaris muscle. As a consequence, there is hypertrophic growth of the plantaris muscle. We used this model to study the molecular mechanisms regulating skeletal muscle hypertrophy. Aged skeletal muscle demonstrates blunted hypertrophic growth in response to functional overload. We hypothesized that an alteration in gene expression would contribute to the blunted hypertrophic response observed with aging. However, the difference in gene expression was modest, with cluster analysis showing a similar pattern of expression between the two groups. Despite ribosomal protein gene expression being higher in the aged group, ribosome biogenesis was significantly lower in aged compared with young skeletal muscle in response to the hypertrophic stimulus (50% versus 2.5-fold, respectively). The failure to fully up-regulate pre-47S ribosomal RNA (rRNA) expression in old skeletal muscle undergoing hypertrophy indicated ribosomal DNA transcription by RNA polymerase I was impaired. Contrary to our hypothesis, the findings of the study suggest that impaired ribosome biogenesis was a primary factor underlying the blunted hypertrophic response observed in old skeletal muscle rather than dramatic differences in gene expression. As it appears ribosomal biogenesis may limit muscle hypertrophy, we assessed the dynamic changes in global transcriptional output during muscle hypertrophy, as the majority of global transcription is dedicated to ribosome biogenesis during periods of rapid growth. Metabolic labeling of nascent RNA using 5-ethynyl uridine permitted the assessment of cell type specific changes in global transcription and how this transcription is distributed within the myofiber. Using this approach, we demonstrate that myofibers are the most transcriptionally active cell-type in skeletal muscle, and furthermore, myonuclei are able to dramatically upregulate global transcription during muscle hypertrophy. Interestingly, the myonuclear accretion that occurs with hypertrophy actually results in lower transcriptional output across nuclei within the muscle fiber relative to sham conditions. These findings argue against the notion that nuclear accretion in skeletal muscle is necessary to increase the transcriptional capacity of the cell in order to support a growth response.

Chapter 1 of this work focuses on alternative splicing of titin as a proof of concept therapy for treating diastolic dysfunction and restrictive filling in a genetic murine model (Ttn^(ΔIAjxn)). The Ttn^(ΔIAjxn) mouse has increased strain on the spring region of titin and acts as a mechanical analogue of the titin-based increase in passive myocardial stiffness found in patients with heart failure and preserved ejection fraction (HFpEF). HFpEF is a complex disease characterized by diastolic dysfunction, exercise intolerance, and concentric hypertrophic remodeling. Approximately half all of heart failure patients suffer from diastolic dysfunction, however, no effective therapy exists for treating this pervasive syndrome. Titin, the largest known protein and molecular spring in the heart, has emerged as a prime candidate for therapeutic targets aimed at restoring compliance to the sarcomere in order to improve diastolic function. Titin has two main cardiac isoforms that are regulated by alternative splicing; the smaller N2B isoform (~3.0 MDa) and the larger more compliant N2BA isoform (~3.3 MDa). Diastolic stiffness of the left ventricle is dependent upon the N2BA:N2B isoform ratio. In the first half of this work, we modified these two primary isoforms by inhibiting the known titin splicing factor Rbm20. We demonstrate that Rbm20 reduction restores diastolic function, improves exercise tolerance and attenuates afterload induced pathologic remodeling of the left ventricle in Ttn^(ΔIAjxn) mice.The work in chapter 2 is focused on studies using the previously published N2B knock out (KO) murine model. The N2B spring element found in cardiac titin's I-band region has been proposed as a sensor and signaling "hot spot" in the sarcomere. This study investigates the role of titin's cardiac specific N2B element as a mechano-sensor for stress and strain induced remodeling of the heart. The N2B KO mouse was subjected to a variety of stressors including transverse aortic constriction (TAC), aortocaval fistula (ACF), chronic swimming, voluntary running and isoproterenol stimulation. Our data revealed that the N2B element is essential in preload stimulated cardiac hypertrophy as well as remodeling due to beta-adrenergic stress. Cardiac hypertrophy is a common maladaptive feature of heart failure patients and the mechanical triggers that determine pathologic growth are not well understood. My work in the N2B KO mouse reveal titin's important role in cardiac remodeling.

Myocyte hypertrophy is the major compensatory response of the heart to chronic stress. It is induced by the activation of a network of interdependent, intracellular signaling pathways.1 An important pathway activated during the hypertrophic response is the calcineurin Abeta-NFATc transcription factor pathway.2 Our laboratory has recently discovered that calcineurin Abeta and NFATc transcription factors can associate with the scaffold protein mAKAPbeta.3 mAKAPbeta is a scaffold protein that forms a multimolecular signalosome located to the nuclear envelope of cardiac myocytes. Preliminary data demonstrate that calcineurin Abeta binds to a specific site on mAKAPbeta that lacks any of the consensus calcineurin binding sequences previously described. In this report, it is shown that a peptide, which contains the mAKAPbeta -calcineurin Abeta binding domain, associates with calcineurin Abeta in a calcium/calmodulin dependent manner. In addition, the binding of this mAKAPbeta peptide to calcineurin Abeta has no effect on calcineurin?s phosphatase activity. In fact, calcineurin Abeta bound to this mAKAPbeta peptide is catalytically active and capable of dephosphorylating NFAT. This is novel since other scaffold proteins that associate with calcineurin Abeta have been reported to inhibit its phosphatase activity. Furthermore, in our laboratory it has been shown that mAKAPbeta is required for both the nuclear translocation of NFATc and the induction of myocyte hypertrophy in vitro.4 In this report it is demonstrated that inhibition of calcineurin Abeta association to mAKAPbeta affects NFATc phosphorylation state and attenuates the norepinephrine induced hypertrophic response in primary neonatal cardiac myocytes. This study supports the hypothesis that the formation of multimolecular signaling complexes, like the mAKAPbeta signalosome, is necessary for the integration and fidelity of signal transduction involved in physiological processes like hypertrophy. Although hypertrophy is an adaptive response; it is often accompanied by maladaptive remodeling of the heart that can result in heart failure, a leading cause of death in the United States. Research in the signaling complexes involved in myocyte hypertrophy, like the mAKAPbeta signalosome, may lead to the development of novel treatments for pathologic hypertrophy and heart failure.

Increases in force production in response to isometric training typically occur at or around the joint angles adopted during the training, but the mechanisms underpinning this have not yet been fully elucidated. This PhD thesis project investigated the mechanisms underpinning joint angle-specific strength changes after isometric training, focussing on muscle region-specific cross-sectional area (CSA), muscle fascicle length (Lf) and muscle activation adaptations. For this, the validity and reliability of a two-dimensional extended-field-of-view ultrasonography (EFOV) method for measuring muscle CSA (Study 1) and Lf (Study 2) were examined. Small standard errors of measurement (SEM) and high intra-class correlations (ICCs) were found for CSA measurements (0.6-1.2% and 0.95-0.99, respectively) at proximal and mid-thigh (30, 40 and 50% of the distance from the superior border of the patella to the medial aspect of anterior superior iliac spine) but not distal sections and CSA measurements were very similar to those obtained using computed tomography scanning. Small SEMs and high ICCs were also obtained for Lf measurements (0.8% and 0.95, respectively), and they were accurate when compared to directly-measured swine muscle fascicles. Nonetheless, because of the time required for EFOV CSA scanning and its unreliability for the distal quadriceps (despite a high ICC, the 95% CI of ICC at 20% section = -0.04-0.99), MRI was used for CSA measurement in the subsequent study. The third study aimed to examine joint angle-specific neuromuscular adaptations in response to isometric knee extension training at short (SL; !knee = 38.1 ± 3.7°) versus long (LL; !knee = 87.5 ± 6.0°) muscle lengths. Sixteen men trained three times a week for six weeks at a knee angle at which peak muscle force (i.e. quadriceps torque/moment arm) was 80% of the peak force obtained at the optimum joint angle. Clear joint angle specificity was seen in SL (force increased 13.4 ± 2.4% at 40°), which was associated with an increase in VL EMG around the training (40°; 26.4 ± 15.5%) and adjacent (50°; 22.5 ± 14.9%) angles, without a shift in the electrically evoked force-angle relationship or changes in muscle size. In contrast, increases in force in LL occurred at angles further from the training angle and varied between subjects. Also, muscle volume and CSA increased significantly and the changes in CSA of specific muscle regions were correlated with the changes in peak force produced at both 30° and at 100°. This occurred with small changes in vastus lateralis (VL) and rectus femoris (RF) muscle EMG activity and no detectable change in coactivation, thus selective regional muscle hypertrophy was most associated with the direction of shift in the force-length relationship. A small (5.4 ± 1.4%) and similar increase in Lf was found in both groups, which was not associated with angle-specific force changes. The effect of isometric training on the concentric torque-velocity relationship was examined in Study 4 to determine whether the isometric training influenced dynamic force production. Isokinetic torque at seven velocities (30, 60, 90, 120, 180, 240 and 300°"s-1) was assessed at weeks 0, 3 and 6. Torque increased only in LL, and only at slow angular velocities (30 - 120°"s-1). The change in torque correlated well with changes in VL, VM and RF CSA, although there was little relationship with Lf. There was no change in angle of peak isokinetic torque. These results reveal a different mechanism of joint angle–specific adaptation between training at short versus long muscle lengths; neural adaptations underpinned changes after training at short quadriceps lengths but muscular (hypertrophic) changes predominated after training at long lengths. Importantly, clear angle specificity was only observed after training at the short length, although muscle mass acquisition and improvements in dynamic muscle force production were elicited only after training at longer lengths. Thus, although specificity is reduced, greater functional benefit appears to be derived after training at longer lengths. Further research is required to determine why some individuals improved force production at shorter muscle lengths after training only at longer muscle lengths and whether such ‘nonspecificity’ can be predicted before training.

Orientador: Antonio Carlos Cicogna
Resumo: Introdução: Diversos modelos experimentais têm avaliado o processo de remodelação cardíaca (RC); dentre eles, destaca-se a indução à estenose aórtica supravalvar (EAo). Os mecanismos fisiopatológicos responsáveis pela depressão da função cardíaca incluem alterações no trânsito de cálcio (Ca2+) e em suas proteínas regulatórias. O treinamento físico (TF) tem sido utilizado na terapêutica das cardiopatias. Na patologia cardíaca por sobrecarga pressórica, o TF restaura, total ou parcialmente, a atividade e/ou expressão das proteínas regulatórias do trânsito de Ca2+, otimizando o fluxo de Ca2+ intracelular e atenuando o prejuízo funcional cardíaco. Objetivo: Analisar a participação do trânsito de Ca2+ e suas proteínas reguladoras na melhoria da função cardíaca de ratos com EAo e disfunção ventricular pelo TF. Material e Métodos: Ratos Wistar machos (70-90 g), submetidos à cirurgia de EAo, foram divididos em dois grupos: controle operado (Sham) e EAo. Após 18 semanas da cirurgia, foi analisada função cardíaca para redistribuição dos grupos: não expostos ao TF (Sham, n= 36 e EAo, n= 29) e treinados (ShamTF, n= 33 e EAoTF, n= 32) durante 10 semanas. O treinamento físico aeróbio (TFa) em esteira foi realizado com velocidade equivalente ao limiar de lactato, obtida durante os testes de esforço (inicial, 4a e 7a semanas e final). A RC foi avaliada por ecocardiografia, músculo papilar e cardiomiócito isolados e macroscopia post mortem. O trânsito de cálcio miocárdico foi analisado pela e... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Introduction: Several experimental models have been proposed for the study of cardiac remodeling (CR); among them, the induction of supravalvular aortic stenosis (AoS). The pathophysiological mechanisms responsible for the cardiac function depression include changes in calcium (Ca2+) and its regulatory proteins. Exercise training (ET) has been used in the management of cardiopathies. In cardiac pathology due to pressure overload, ET completely or partially restores the activity and/or expression of regulatory proteins of Ca2+ handling, optimizing intracellular Ca 2+ flow and attenuating cardiac functional impairment. Objective: To analyze the participation of Ca2+ handling and its regulatory proteins in the improvement of the cardiac function of rats with aortic stenosis and ventricular dysfunction by ET. Material and Methods: Male Wistar rats (70-90 g) submitted to supravalvular aortic stenosis (AoS) were divided into two groups: operated control (Sham) and aortic stenosis (AoS). After 18 weeks of the surgical procedure, cardiac function analysis was performed for redistribution of the groups: non-exposed to exercise training (Sham, n = 36 and AoS, n = 29) and trained (ShamET, n = 33 and AoSET, n = 32) for 10 weeks. The treadmill exercise training was performed with a velocity equivalent to the lactate threshold, obtained during effort tests (initial, 4th and 7th weeks, and final). CR was evaluated by echocardiography, papillary muscle and cardiomyocyte isolated and postmort... (Complete abstract click electronic access below)
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An arginine (R) to a glycine (G) mutation at position 145 in the highly reserved inhibitory domain of cardiac troponin I (cTnI) is associated with hypertrophic cardiomyopathy (HCM), an autosomal dominant disease characterized by left ventricular hypertrophy. An arginine (R) to tryptophan (W) mutation at the same position in cTnI is associated with restrictive cardiomyopathy (RCM), a disease characterized by diastolic dysfunction with normal left ventricular size and normal systolic function. In this study we addressed the functional consequences of the human cardiac troponin I (hcTnI) HCM R145G mutation and hcTnI RCM R145W mutation in transgenic mice. Simultaneous measurements of the ATPase activity and force in skinned papillary fibers from hcTnI R145G transgenic mice (Tg-R145G) versus hcTnI wild type transgenic mice (Tg-WT) showed a significant decrease in the maximal Ca2+ activated force without changes in the maximal ATPase activity and an increase in the Ca2+ sensitivity by both ATPase activity and force development. No difference in the cross-bridge turnover rate was observed at the same level of cross-bridge attachment (activation state) showing that changes in Ca2+ sensitivity were not due to changes in cross-bridge kinetics. Energy cost calculations demonstrated higher energy consumption in Tg-R145G fibers compared to Tg-WT fibers. The addition of 3mM BDM at pCa 9.0 showed that there was approximately 2~4 percent of force generating cross-bridges attached in Tg-R145G fibers compared to less than 1.0 percent in Tg-WT fibers, suggesting the mutation impairs the ability of the cardiac troponin complex to fully inhibit cross-bridge attachment under relaxing conditions. Prolonged force and intracellular [Ca2+] transients in electrically stimulated intact papillary muscles were observed in Tg-R145G compared to Tg-WT. These results suggest that the phenotype of HCM is most likely caused by the compensatory mechanisms in the cardiovascular system which are activated by: 1) higher energy cost in the heart resulting from a significant decrease in average force per cross-bridge; 2) incomplete relaxation (diastolic dysfunction) caused by prolonged [Ca2+] and force transients; and 3) an inability of the cardiac TnI to completely inhibit activation at low levels of diastolic Ca2+ in Tg-R145G. Simultaneous measurements of the ATPase activity and force in transgenic skinned papillary fibers from hcTnI R145W transgenic mice (Tg-R145W) versus Tg-WT showed that there was a ~13 to ~16 percent increase in the maximal Ca2+ activated force and ATPase activity, respectively. The rate of dissociation of force generating cross-bridges (g) and energy cost (ATPase/force) was the same in all groups of fibers. These results suggest that the increase in force and ATPase activity is associated with an increase in the number of force generating cross-bridges attached at all activation levels. Additionally, there was a large increase in the Ca2+ sensitivity of force development and ATPase activity. In intact fibers, the mutation caused prolonged force and intracellular [Ca2+] transients, as expected due to the increased Ca2+ sensitivity (slower dissociation rate of Ca2+ from cTnC). The above cited results suggest that: 1) there would be an increase in resistance to ventricular filling during diastole resulting from the prolonged force and Ca2+ transients, especially at high heart rates; 2) there would be a decrease in ventricular filling (diastolic dysfunction); and 3) an increase in contractility during systole that would off-set the negative effect of a decrease in diastolic filling on ventricle stroke volume thus allowing the heart to maintain normal stroke volume despite the compromise in RCM (Tg-R145W) heart.

Introdução: A correção anatômica da transposição das grandes artérias após o período neonatal demanda a preparação prévia do ventrículo subpulmonar, com bandagem do tronco pulmonar, para induzir a hipertrofia ventricular. Estudos experimentais prévios demonstraram que a sobrecarga sistólica intermitente determina uma hipertrofia ventricular mais eficiente, em relação à bandagem convencional (fixa) do tronco pulmonar. Os mecanismos adaptativos envolvidos no retreinamento do ventrículo subpulmonar ainda não estão completamente estabelecidos, pois se sabe que, além da hipertrofia e hiperplasia das células contráteis, também células do interstício e vasos sofrem alterações fenotípicas. Permanece indefinida a taxa ideal de incremento, tanto da matriz extracelular quanto da vascularização do miocárdio na situação do retreinamento ventricular, para suportar a resistência sistêmica. Objetivo: Avaliar a adaptação do ventrículo subpulmonar no que se refere a apoptose e estímulo à neovascularização miocárdica em resposta à sobrecarga pressórica contínua versus intermitente, obtida pela bandagem ajustável do tronco pulmonar de cabritos jovens. Método: Foram utilizados 21 cabritos hígidos, com idade de 30 a 60 dias e pesos comparáveis, divididos em três grupos: Controle (n = 7, sem sobrecarga sistólica), Contínuo (n = 7, sobrecarga sistólica contínua do VD), Intermitente (n = 7, 12 horas/dia de sobrecarga sistólica intermitente do VD). A sobrecarga sistólica do VD foi mantida por 96 horas no grupo Contínuo e por quatro períodos de 12 horas, alternados com 12 horas de descanso, no grupo intermitente. Os animais do grupo Controle foram submetidos ao implante do dispositivo de bandagem, o qual foi mantido desinsuflado. As medidas hemodinâmicas foram tomadas diariamente, antes e após o ajuste da sobrecarga sistólica. Avaliações ecocardiográficas foram realizadas no pré-operatório e no final do protocolo de estudo. Após 96 horas de estudo, os animais foram mortos para avaliação dos parâmetros morfológicos (peso e conteúdo de água das massas cardíacas e análise imuno-histoquímica da apoptose e da expressão do VEGF). Resultados: Ao final do protocolo, o ecocardiograma revelou uma diferença significativa da espessura do VD no grupo Intermitente (+129,2%), quando comparado ao grupo Contínuo (+58,2%; p < 0,001) e de ambos os grupos de estudo quando comparados ao grupo Controle (p < 0,001). Sob a análise morfológica, ambos os grupos de estudo apresentaram ganho de magnitude semelhante nas massas do VD (Intermitente: + 115,8%; Contínuo: + 90,8%; p < 0,0001) e do septo (Intermitente: +55,8%; Contínuo: + 45,4%; p < 0,047), em relação ao grupo Controle, apesar do menor tempo de sobrecarga pressórica no grupo Intermitente. O protocolo de sobrecarga sistólica do VD não influenciou a massa muscular do VE. Houve um discreto aumento do conteúdo de água do VD (Contínuo: +3,5%, Intermitente: +4,6%) e do septo (ambos os grupos de estudo: +3,5%) em relação ao grupo Controle (p < 0,002). A expressão do VEGF foi maior no VD do grupo Intermitente (2,89% ± 0,41%; p=0,005) em relação ao VD dos demais grupos (Controle: 1,43% ± 0,18%; Contínuo: 1,80% ± 0,19%). A expressão desta molécula no miocárdio do VD do grupo Intermitente foi também maior que o do VE e septo dentro do mesmo grupo (p < 0,050). Não houve diferença na expressão do VEGF das demais massas cardíacas (VE: p > 0,252; Septo: p > 0,740). Em relação à apoptose, não foram observadas diferenças significativas no miocárdio do VD dos três grupos (Caspase: p=0,784; TUNEL: p=0,374). Conclusões: Ambos os grupos de estudo desenvolveram hipertrofia miocárdica do VD, não acompanhada de edema miocárdico importante ou apoptose. No entanto, a sobrecarga sistólica intermitente promoveu maior expressão do VEGF no miocárdio do VD. Esta associação entre sinalização de proliferação vascular e hipertrofia tem implicações importantes quando se objetiva preparar um ventrículo para suportar pressões sistêmicas, uma vez que o desejável é que a proliferação vascular ocorra de forma sustentada, permitindo uma hipertrofia do VD mais eficiente
Introduction: Surgical correction of transposition of the great arteries beyond the neonatal period needs a previous pulmonary artery band to promote left ventricular hypertrophy thereby preparing the ventricle. Experimental studies have demonstrated that intermittent systolic overload causes a more efficient ventricular hypertrophy, as compared to traditional pulmonary artery banding. The adaptive mechanisms involved in the subpulmonary ventricle retraining are not completely established. Nevertheless, besides the hypertrophy and/or hyperplasia of the contractile cardiomyocytes, noncontractile cells (vascular and interstitial) from the stimulated ventricle also present structural phenotype changes. It remains unclear the ideal increasing rate of the myocardial interstitium as well as capillary vessel proliferation in the process of ventricular retraining before undertaking the arterial switch. Objective: This study sought to assess adaptive changes of the subpulmonary ventricle in regards to vascular endothelial growth factor (VEGF) expression and apoptosis in young goats submitted to continuous versus intermittent systolic overload by means of an adjustable pulmonary artery band. Methods: 21 young goats were separated into 3 groups: Control (no systolic overload), Continuous (96-hour continuous systolic overload), and Intermittent (four 12-hour periods of systolic overload paired with a 12-hour resting period). Systolic overload was adjusted to achieve a 0.7 RV / aortic pressure ratio. Hemodynamic evaluations were performed before and after systolic overload every day postoperatively. Echocardiograms were obtained preoperatively and at the end of protocol. After the study period, the animals were humanely killed for morphologic assessment, apoptosis and vascular endothelial growth factor (VEGF) expression. Results: Echocardiography revealed a marked increase in RV wall thickness in the Intermittent group (+129.2%), compared with the Continuous group (+58.2%; p<0.001), as well as both trained groups compared to Control group (p < 0.001). Regardless of the shorter systolic overload exposure of Intermittent group, both study groups had a similar increase in RV mass (Intermittent: + 115.8%; Continuous: +90.8%; p < 0.001), and septal mass (Intermittent: + 55.8%; Continuous: + 45.4%; p < 0.047), compared with the Control group. No significant changes in the left ventricle mass were seen. There was a negligible but significant increase in water content of RV (Continuous: +3.5%, Intermittent: +4.6%) and septal masses (both study groups: +3.5%) compared with that in the Control group (p < 0.002). RV VEGF expression was greater in the Intermittent group (2.89% ± 0.41%) than in the Continuous (1.80% ± 0.19%) and Control (1.43% ± 0.18%) groups (p < 0.023). VEGF expression in the myocardium of the right ventricle in the Intermittent group was also greater than that in the left ventricle and septum within the same group (p < 0.050). There was no significant difference in VEGF expression between the other cardiac sections or within the Control and Continuous groups. Regarding apoptosis, there were no significant changes in the RV myocardium of the three groups (Caspase: p=0,784; TUNEL: p=0,374). Conclusions: Both study groups have developed RV hypertrophy with no apoptosis or relevant myocardial edema. Nevertheless, intermittent systolic overload causes upregulation of VEGF expression in the subpulmonary ventricle, an adaptation that provides a mechanism for increased myocardial perfusion during the rapid myocardial hypertrophy of young goats. The association of the marked increase in RV mass and increased angiogenesis signaling has an important implication on the subpulmonary ventricle retraining protocol by promoting a compensatory growth of the coronary vasculature, allowing for a more efficient hypertrophy

碩士
國立臺灣大學
動物學研究所
96
Voltage-gated T-type Ca2+ current (T-current) is temporarily recorded in cardiac myocytes during embryonic and postnatal period in some rodents (Leuranguer et al., 2000; Niwa et al., 2004) and was found linearly correlated with growth rate in rat of both sexes (Xu and Best, 1992). The growth of body weight and heart size has been well studied to be affected by chronically elevated growth hormone (GH) through the action of Insulin-like growth factor-1 (IGF-1) (Boguszewski et al., 1997; Ong et al., 2002; Xu and Best, 1991). Moreover, through the approach of patch-clamp, IGF-1 was found to be able to increase the current density of T-channels (Piedras-Renteria et al., 1997). Collectively, physiological cardiac hypertrophy in athletes is associated with increased cardiac IGF-1 formation, implying that T-channel might play a role in the physiological cardiac hypertrophy formation. To test the hypothesis that T-channels are involved in that cardiac remodeling during physiological cardiac hypertrophy, CaV3.2 T-type calcium channel deficient mice (CaV3.2-/-) were subjected to swimming training for 3 weeks and the development of cardiac hypertrophy was examined with echocardiography. At the basal level, there is no significant difference between wild type (WT) and CaV3.2-/- left ventricular mass (LVM) but after 3 weeks of swimming, WT showed a significant increase of LVM (0.11 ±0.0028 g (WT non-swim, n=7) and 0.13 ± 0.0029 g (WT swim, n=7, p<0.001). In contrast, swimming-induced physiological cardiac hypertrophy was blunted in CaV3.2-/-, the LVM were 0.1099 ± 0.005 (CaV3.2-/- non-swim, n=5) and 0.1036 ± 0.0028 (CaV3.2-/- swim 21ds, n=5, p=0.3). These findings suggest that CaV3.2 is necessary for triggering swimming-induced physiological cardiac hypertrophy.

The ability to generate cardiomyocytes from either embryonic stem cells or induced pluripotent stem cells provides an unprecedented opportunity to establish human in vitro models of cardiovascular disease as well as to develop platforms for the testing of novel cardiac therapeutics. We designed two different platforms, a biowire platform and post deflection platform, to generate engineered heart tissues (EHTs) to study a fundamental process in cardiomyocytes: hypertrophy. Both pathological and physiological hypertrophy was studied in order to garner a better understanding of each process. Physiological hypertrophy characteristics were observed using the biowire platform seen in improved myofibril alignment and downregulation of fetal genes. When electrical stimulation was added, a rate dependent effect on sarcomere maturation was observed by the increased frequency of I-bands and H-zones. Certain hallmark features of pathological hypertrophy, such as upregulation of brain natriuretic peptide and sarcomere structure breakdown, were recapitulated when EHTs were treated with isoproterenol.

The purpose of this study was to compare the myocardial structure and function among endurance athletes (n.12), powerlifters/steroid users (n=5), powerlifters/non-steroid users (n=6), and sedentary controls (n=4). All subjects had a M-mode echocardiographic examination of their left ventricles under resting conditions. The echocardiographic measurements recorded and analyzed were of the left ventricular posterior wall at diastole and systole, left ventricular internal diameter at diastole and systole, and inter-ventricular septal thickness at diastole and systole. Myocardial function measurements consisting of left ventricle ejection time, left ventricular mass, mean ventricular contractile force, and percent fractional shortening were also recorded and analyzed. A One Way Analysis of Variance was used to analyze the data for statistical significance. A Tukey's HSD post-hoc test was used to determine statistical significance between the groups. A significant difference (p =0.02) was found for inter-ventricular septal thickness during diastole. All three athletic groups had significantly thicker inter-ventricular septa' thickness during diastole as compared to the controls. Power lifters/steroid users had the thickest inter-ventricular septal thickness (18.7 mm), followed by endurance athletes (18.6 mm), and powerlifters/nonsteroid users (16.5 mm). Overall, powerlifters/steroid users had the thickest walls at systole and diastole, while endurance athletes had the greatest internal diameters relative to the size of the left ventricle. Statistically significant differences among the groups were found for all four myocardial functional parameters: left ventricular ejection time (p = 0.03), left ventricular mass (p = 0.002), mean ventricular contractile force of (p 0.0013), and percent fractional shortening (p = 0.05). Power lifters/steroid users had the fastest left ventricular ejection times, largest left ventricular mass, greatest mean ventricular contractile force, and greatest percent fractional shortening. Endurance athletes had the slowest left ventricular ejection times, second largest left ventricular mass, lowest mean ventricular contractile force, and third lowest percent fractional shortening. The results indicated that not all individuals participating in high level endurance or powerlifting training and competition demonstrated complete adaptations in myocardial structure and function. Power lifters/steroid users however, demonstrated myocardial functional adaptations that were significantly different from powerlifters/non-steroid users, endurance athletes, and controls. The results of this study cannot attribute these changes either to the use of large amounts of anabolic steroids, or long-term, high-intensity training and competition in powerlifting. However, the study identified alterations in myocardial functions in powerlifters/steroid users, and contributes to the existing body of knowledge regarding the use of anabolic steroids by athletes.
Graduation date: 1990

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School of Physical Education, Sport, and Exercise Science

博士
臺北醫學大學
保健營養學研究所
102
Herbal supplements and food factors are important resources to investigate about muscle hypertrophy or protein synthesis. We investigated Astragalus membranaceus (AM) whether those herbal supplements induce hypertrophy in myotubes through the phosphatidylinositol 3-kinase (PI3K)/Akt (also termed PKB)/mammalian target of the rapamycin (mTOR) pathway. Then, we study the safety assessment and exercise ability of AM supplements which can promote skeletal muscle hypertrophy. The results revealed that AM can promote hypertrophy in myotubes through the PI3K/Akt/mTOR pathway. Biochemical parameters and histopathological examination revealed no toxic effect of 6-week AM (0.615 and 3.075 g / kg B.W. / day) administration in training ICR mice. Furthermore, AM supplement (2.8 g / day, contain total astragalosides 1.455 mg / g ) can enhance serum insulin-like growth factor-1 (IGF-1) concentrations and increase the oxygen content of muscle tissue in human. According to our study, we suggest that AM may be used as a candidate nutritional supplement to promote athletic performance.

Experiments were conducted to investigate the role of free radicals in exercise induced cardiac adaptations and to determine if statin administration would adversely affect cardiac adaptations to exercise. In the first experiment myocardial antioxidant enzymes, cardiac function and cardiac hypertrophy were assessed following a chronic exercise protocol previously used by our lab. MPG effectively reduced myocardial oxidative stress and activation of the signaling proteins Akt and S6 following an exercise bout. Skeletal muscle mitochondria content increased to similar levels in E and E+MPG. Similar increases (P<0.05) in both exercised groups were observed for heart wt and heart wt to body wt ratio. Cardiac function at the high workload improved in E vs S as indicated by higher (P<0.05) peak systolic pressure (SP), cardiac output (CO), coronary flow, COxSP and mechanical efficiency (COxSP/VO2). MPG prevented these exercise-induced functional improvements. This study provides evidence that free radicals do not play a role in the development of exercise-induced cardiac hypertrophy, however, they are involved in functional cardiac adaptations, which may be mediated through the PI3K/Akt pathway. In the second experiment a similar exercise protocol was used to determine if statins which have been shown to prevent pathological forms of cardiac hypertrophy, would be detrimental to exercise induced cardiac adaptations. In addition to the sedentary and exercise groups sedentary+statin and exercise+statin groups were assessed. Hearts were isolated and perfused and assessed for function at low and high workloads. Exercise treatment resulted in cardiac hypertrophy in absolute and relative terms to a similar extent in statin-treated and untreated exercised rats. Additionally it resulted in significant functional increases for SP, CO, COxSP, VO₂, and EFF in both exercised groups. In conclusion, these studies provide evidence that exercise in the cold is a valid model for physiological cardiac hypertrophy and that pathological and physiological cardiac hypertrophy signal through different pathways due to the fact that two well established treatments (mpg and statins) that prevent pathological cardiac hypertrophy did not affect exercise induced cardiac hypertrophy.
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