Myostatin (GDF-8) is the chief chalone in skeletal muscle and negatively controls adult skeletal muscle growth. The role of myostatin during overload-induced hypertrophy of adult muscle is unclear. We tested the hypothesis that overloaded adult rodent skeletal muscle would result in reduced myostatin protein levels. Overload-induced hypertrophy was accomplished by unilateral tenotomy of the gastrocnemius tendon in male adult Sprague-Dawley rats followed by a two-week period of compensatory overload of the plantaris and soleus muscles. Western blot analysis was performed to evaluate changes in active, latent and precursor myostatin protein levels. Significant hypertrophy was noted in the plantaris (494 ± 29 vs. 405 ± 15 mg, p < 0.05) and soleus (289 ± 12 vs. 179 ± 37 mg, p < 0.05) muscles following overload. Overloaded soleus muscle decreased the concentration of active myostatin protein by 32.7 ± 9.4% (p < 0.01) while the myostatin precursor protein was unchanged. Overloaded plantaris muscle decreased the concentration of active myostatin protein by 28.5 ± 8.5% (p < 0.01) while myostatin precursor levels were reduced by 17.5 ± 5.9% (p < 0.05). Myostatin latent complex concentration decreased in the overloaded soleus and plantaris muscle by 15.0 ± 5.9% and 70.0 ± 2.3% (p < 0.05), respectively. These data support the hypothesis that the myostatin signaling pathway in overloaded muscles is generally downregulated and contributes to muscle hypertrophy. Plasma concentrations of total and active myostatin proteins were similar in overloaded and control animals and averaged 8865 ± 526 pg/ml and 569 ± 28 pg/ml, respectively. Tissue levels of BMP-1, an extracellular proteinase that converts myostatin to its active form, also decreased in overloaded soleus and plantaris muscles by 40.4 ± 12.9% and 32.9 ± 6.9% (p < 0.01), respectively. These data support the hypothesis that local, rather than systemic, regulation of myostatin contributes to the growth of individual muscles, and that an association exists between the extracellular matrix proteinase BMP-1 and the amount of active myostatin in overloaded muscles.

Background: A major problem in the treatment of human hypertension is the late diagnosis of hypertension and, hence, the delayed start of treatment. Very often, hypertension has existed for a long time and cardiac damage has already developed. Therefore, we tested whether lateonset antihypertensive treatment is effective in lowering blood pressure (BP) and in reducing or even preventing left ventricular hypertrophy and fibrosis. Methods: Twenty-one male 60-week-old spontaneously hypertensive rats (SHR) were included. Fourteen rats received oral treatment with captopril (CAP) either as monotherapy or combined with nifedipine (CAP + NIF) over 22 weeks. Seven untreated SHR served as controls. We examined the therapeutic effects on BP, heart weight and histological and biochemical markers of left ventricular remodeling and fibrosis. Results: At 82 weeks of age, BP was reduced in the CAP and CAP + NIF groups by 44 and 51 mmHg, respectively (p < 0.001), but not in untreated controls. Despite the late therapy start, cardiac hypertrophy and fibrosis were attenuated compared to controls. Both treatments reduced heart weight by 1.2 mg/g (25%, p = 0.001) and collagens I and III by 66% and 60%, respectively (p < 0.001), thus proving nearly equivalent cardioprotective efficacy. Conclusion: These data clearly emphasize the benefit of antihypertensive treatment in reducing BP and mitigating the development of cardiac damage even when treatment is started late in life.

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<p>Chronic resistance training leads to muscle hypotrophy in a wide range of populations however most resistance training studies are relatively small in sample size</p> <p>Three studies were conducted to better understand the sources of this variability. The first study employed a unilateral resistance training model to test the effects of relative training load and volume on the magnitude of hypertrophy and strength gains. This study showed that high relative training loads were no better than low training loads at inducing muscle hypertrophy provided that each set was performed to the point of muscular exhaustion. In agreement with previous finding, strength gains were greatest with the highest loads.</p> <p>The next two studies attempted to correlate various putative regulators of muscle hypertrophy with the magnitude of hypertrophy after 16 weeks of training in 23 subjects. Study two showed no association between the acute responses of testosterone, GH or IGF-1 and muscle hypertrophy but did show associations with androgen receptor content and acute phosphorylation of p70S6K. This suggests that local rather than systemic processes are the most important regulators of muscle hypertrophy.</p> <p>The third study tested whether the acute post exercise protein synthetic response to a single bout of resistance exercise is related to the magnitude of hypertrophy following training in the same subjects. Although previous work has shown that acute post exercise protein synthetic response is qualitatively similar to the magnitude of hypertrophy after chronic training with similar manipulations in different subjects, we did not see any relationship.</p> / Doctor of Philosophy (PhD)

The role of T-type calcium channels (TTCCs) in the heart is unclear. TTCCs are transiently expressed throughout the neonatal heart during a period of rapid cardiac development. A few weeks postnatally, TTCCs are no longer found in ventricular myocytes (VMs) and calcium influx via TTCCs (ICa,T) is only detected in the SA node and Purkinje system. However, pathologic cardiac stress is associated with re-expression of TTCCs in VMs. Whether ICa,T in this setting promotes cardiac growth or exacerbates cardiac function is a topic of debate. The focus of this thesis work was to examine the effect of TTCC re-expression in the normal and diseased myocardium. Our experiments were performed in a transgenic mouse model with inducible, cardiac-specific expression of α1G TTCCs. While both the α1G and α1H TTCC subtypes re-appear during cardiac disease, we specifically evaluated the effects of α1G TTCCs since mRNA levels of this TTCC subtype are markedly elevated during cardiac pathology. We found that transgenic mice with α1G overexpression had robust ICa,T with biophysical properties similar to those published in previous studies. α1G mice had a small increase in cardiac function and showed no evidence of cardiac histopathology or increased mortality. These findings were in contrast to the phenotype of transgenic mice with augmented L-type calcium channel (LTCC) activity secondary to overexpression of the β2a regulatory subunit. While the magnitude of calcium influx in α1G and β2a VMs was similar, we found that cardiac contractility of β2a mice was significantly greater than α1G mice. Also, β2a mice had significant cardiac fibrosis, myocyte death, and premature lethality compared to the benign phenotype of α1G mice. We showed that the phenotypic differences are likely related to the differential spatial localization of T- and LTCCs. Whereas α1G TTCCs were principally localized to the surface sarcolemma, LTCCs were primarily found in the transverse tubules in close proximity to the sites of sarcoplasmic reticulum calcium release. We evaluated the effect of TTCC expression during cardiac disease by inducing myocardial infarction (MI) in α1G mice. Acutely (1-week post MI), α1G mice showed similar worsening of cardiac function and mortality rates compared to control post-infarct mice. However, α1G hearts had smaller infarct sizes which correlated with increased Akt and NFAT activation in α1G than control hearts. After chronic heart failure, i.e. 7- weeks post-infarction, α1G hearts had significant hypertrophic response as determined by increased HW/BW ratio, myocyte cross-sectional area, as well as NFAT and Akt activity. Finally, α1G mice had a small survival benefit than control mice, which while statistically non-significant, suggests that TTCC re-expression does not exacerbate cardiac function as hypothesized by some investigators. We conclude that TTCCs play a minimal role in cardiac function and activate pro-survival signaling pathways in the myocardium. / Physiology

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Motivation - Depression is a mental disorder that has been associated with cardiovascular morbidity and mortality in the Western world. Cardiometablic mechanisms have been implicated as possible intermediating factors in the relationship between depressive symptoms and cardiovascular disease; however this has not yet been determined in black Africans (hereafter referred to as Africans). Aim - The overarching aim of this study was to investigate the relationship between depressive symptoms and cardiometabolic risk. We therefore aimed to assess cardiometabolic function, neuroendocrine responses, inflammatory and haemostatic markers in Africans with depressive symptoms compared to those without symptoms of depression. Methodology - Manuscripts presented in Chapter 2, 3 and 4 utilised data from the cross-sectional, target population multi-disciplinary “Sympathetic activity and Ambulatory Blood Pressure in Africans” (SABPA) study. The participants comprised of 200 African teachers from the Dr Kenneth Kaunda District in North-West province, South Africa. As cardiovascular disease is compromised by a positive HIV status, 19 participants were excluded from further statistical analysis. Stratification was based on the Patient Health Questionnaire 9-item (PHQ-9), which has been validated in a sub-Saharan African setting. PHQ-9 scores > 10 were used to classify participants as having signs of depressive symptoms. Subjects were further stratified by gender (Manuscript 1 and 3) and cortisol responses (Manuscript 2). Cardiometabolic health measures included 24-hour blood pressure, metabolic syndrome markers, neuroendocrine markers [cortisol and 3-methoxy-4-hydroxy-phenylglycol (MHPG)], left ventricular hypertrophy (LVH),inflammatory and haemostatic markers (fibrinogen, C-reactive protein, plasminogen activator inhibitor-1 and D-dimer). Resting 12-lead ECG Cornell Product-Left ventricular hypertrophy (CP-LVH) was measured as a marker of target end-organ damage and cardiovascular dysfunction (Manuscript 1 and 2). Means and prevalence were computed through t-test and Chi-square analysis respectively. Significant differences of mean cardiometabolic measures between depressive symptom status groups were also determined by analysis of covariance (adjusted for traditional cardiovascular risk factors and additional factors as specific per manuscript). Multivariate analysis was used to demonstrate associations between left ventricular hypertrophy (LVH) and cardiometabolic markers in Africans with depressive symptoms (Manuscript 1 and 2) and a logistic regression analysis were performed to examine the association between depressive symptoms and inflammatory/haemostatic factors (Manuscript 3). All subjects who participated gave informed consent, the study was approved by the Ethics Committee of North-West University (NWU-0003607S6), in accordance with the principles outlined by the World Medical Association Declaration of Helsinki of 1975 (revised 2008). Results and conclusions of the individual manuscripts - The aim of the study was to investigate the associations between depressive symptoms and cardiometabolic function including cardiovascular dysfunction. Markers of cardiometabolic function assessed were 24 hour blood pressure measurements, metabolic syndrome markers, neuroendocrine markers [cortisol and 3-methoxy-4-hydroxy-phenylglycol (MHPG)], inflammatory and haemostatic variables (fibrinogen, C-reactive protein, plasminogen activator inhibitor-1 and D-dimer). Manuscript 1, focused on LVH as a marker of cardiovascular dysfunction and metabolic syndrome components as markers of cardiometabolic function. The aim of the study was to assess the associations between LVH and metabolic syndrome (MetS) risk markers in participants with and without depressive symptoms. Results revealed that in African men with depressive symptoms the most significant determinants of LVH were systolic blood pressure (SBP) and the percentage glycosylated haemoglobin (HbA1c). While in African women (with depressive symptoms), this association was determined by low high-density lipoprotein (HDL-cholesterol). The study concluded that in black African men, independent of depressive symptoms, cardiometabolic factors (namely SBP and HbA1c) may be the driving significant factors in the development of cardiovascular diseases. Furthermore, the data showed that depressive symptoms in African women were associated with a measure of target end organ damage, and that this association was driven by a metabolic factor. Manuscript 2, the aim of this manuscript was to examine the relationship between depressive symptoms, neuroendocrine responses [with cortisol and 3-methoxy-phenylglycol (MHPG) as markers] and cardiovascular risk, i.e. LVH. The results revealed that Africans with depressive symptoms demonstrated blunted cortisol and MHPG levels in response to acute mental stress, in comparison to those without symptoms of depression. Additionally, these low cortisol and blunted MHPG responses were associated with LVH in this ethnic group. The conclusion for this manuscript was that, blunted neuroendocrine responses linked depressive symptoms and ECG left ventricular hypertrophy in Africans. When coupled to their hypertensive status, these vasoconstrictive responses (cortisol and MHPG) may underpin the increased long-term depression and vascular disease risk in urban Africans. Manuscript 3, the aim of this manuscript was to investigate the relationship between depressive symptoms and inflammatory/haemostatic markers in a cohort of urban-dwelling black African men and women. Our data demonstrated hypercoagulation vulnerability in African men with depressive symptoms. The African men with signs of depression displayed higher plasminogen activator inhibitor (PAI-1) levels and marginally elevated D-dimer levels. It was concluded that hypercoagulation may partially be the mediating factor between depressive symptoms and cardiovascular risk in African men; a situation that may be exacerbated by hyperkinetic blood pressure. In conclusion, through the assessement of cardiometabolic function and neuroendocrine responses, it seems that Africans withdepressive symptoms are at great risk for cardiovascular related morbidity and mortality, this was particulary evident in the African men (Manuscript 1 and 3). Additionally, it appears that blunted neuroendocrine responses and hypercoagulation could be seen as possible cardiovascular risk markers in Africans with depressive symptoms. / PhD (Physiology), North-West University, Potchefstroom Campus, 2014

Master of Science / Department of Human Nutrition / Denis M. Medeiros / Copper deficiency has been linked with many health problems, among them cardiac hypertrophy. Because of its potential for causing oxidative damage, copper within the cell must be bound to chaperone proteins. In this thesis, we examined the role of dietary copper deficiency in the regulation of select copper chaperone proteins in cardiac tissue of rats. Sixteen weanling male Long-Evans rats were randomized into treatment groups, one group receiving a copper deficient diet (< 1 mg Cu/kg diet) and one group receiving a diet containing adequate copper (6 mg Cu/kg diet) for 5 weeks. Rats were sacrificed and a small blood sample was removed to determine hematocrit. Also, heart and liver tissues were removed for subsequent analysis. Rats fed the copper deficient diet had lower body weights but greater heart weights and heart:body weight. Hematocrit levels and liver copper concentrations were markedly decreased in copper deficient rats. These variables indicated that the copper deficient diet did in fact induce a copper deficiency in these animals. Non-myofibrillar proteins from the hearts were removed and separated by SDS-PAGE. Western Blotting was used to determine the concentrations of CTR1, CCS, Cox17, SCO1, Cox1 and Cox4. No changes were observed in the concentrations of CTR1 and Cox17. CCS and SCO1 were up-regulated as a result of copper deficiency, while Cox1 and Cox4 were both down-regulated. However, use of another antibody against Cox subunits suggested that only the nuclear encoded subunits including subunit IV were decreased, but not subunits I and II. These data provide new insight into the cardiac hypertrophy observed in copper deficiency, which suggests that select chaperone proteins may be up-regulated by a dietary copper deficiency.