Caffeine does not influence persistent inward current contribution to motoneuron firing
- Mackay, Karen, Orssatto, Lucas, Polman, Remco, Van der Pols, Jolieke, Trajano, Gabriel
- Authors: Mackay, Karen , Orssatto, Lucas , Polman, Remco , Van der Pols, Jolieke , Trajano, Gabriel
- Date: 2023
- Type: Text , Journal article
- Relation: Journal of Neurophysiology Vol. 130, no. 6 (2023), p. 1529-1540
- Full Text: false
- Reviewed:
- Description: The purpose of this study was to investigate whether caffeine consumption would change persistent inward current (PIC) contribution to motoneuron firing at increased contraction intensities and after repetitive sustained maximal contractions. Before and after the consumption of 6 mg·kg-1 of caffeine or placebo, 16 individuals performed isometric triangular-shaped ramp dorsiflexion contractions (to 20% and 40% of peak torque), followed by four maximal contractions sustained until torque production dropped to 60% of maximum, and consecutive 20% triangular-shaped contractions. Tibialis anterior motor unit firing frequencies were analyzed from high-density surface electromyograms. PIC contribution to motor unit firing was estimated by calculating the delta frequency (DF) using the paired motor unit technique. Motoneuron peak firing frequencies at 20% and 40% contractions and total torque-time integral during the repetitive sustained maximal contractions were also assessed. DF increased 0.69 peaks per second (pps) (95% CI ¼ -0.98, -0.405; d ¼ -0.87) from 20% to 40% contraction intensities and reduced 0.85 pps (95% CI ¼ 0.66, 1.05; d ¼ 0.99) after the repetitive sustained maximal contractions, regardless of caffeine consumption. Participants produced 337 Nm·s (95% CI ¼ 49.9, 624; d ¼ 0.63) more torque integral during the repetitive sustained maximal contractions after caffeine consumption. A strong repeated-measures correlation (r ¼ 0.61; 95% CI ¼ 0.49, 0.69) was observed between reductions of DF and peak firing frequencies after the repetitive sustained maximal contractions. PIC contribution to motoneuron firing increases from 20% to 40% contraction intensities, with no effect of caffeine (on rested tibialis anterior). Repetitive sustained maximal contractions reduced PIC contribution to motoneuron firing, regardless of caffeine or placebo consumption, evidencing that changes in intrinsic motoneuron properties contributed to performance loss. Caffeine-attenuated reduction of torque production capacity was unlikely mediated by PICs. © 2023 American Physiological Society. All rights reserved.
Involvement of human monogenic cardiomyopathy genes in experimental polygenic cardiac hypertrophy
- Prestes, Priscilla, Marques, Francine, Lopez-Campos, Guillermo, Lewandowski, Paul, Delbridge, Lea, Charchar, Fadi, Harrap, Stephen
- Authors: Prestes, Priscilla , Marques, Francine , Lopez-Campos, Guillermo , Lewandowski, Paul , Delbridge, Lea , Charchar, Fadi , Harrap, Stephen
- Date: 2018
- Type: Text , Journal article
- Relation: Physiological Genomics Vol. 50, no. 9 (2018), p. 680-687
- Full Text:
- Reviewed:
- Description: Hypertrophic cardiomyopathy thickens heart muscles, reducing functionality and increasing risk of cardiac disease and morbidity. Genetic factors are involved, but their contribution is poorly understood. We used the hypertrophic heart rat (HHR), a unique normotensive polygenic model of cardiac hypertrophy and heart failure, to investigate the role of genes associated with monogenic human cardiomyopathy. We selected 42 genes involved in monogenic human cardiomyopathies to study: 1) DNA variants, by sequencing the whole genome of 13-wk-old HHR and age-matched normal heart rat (NHR), its genetic control strain; 2) mRNA expression, by targeted RNA-sequencing in left ventricles of HHR and NHR at 5 ages (2 days old and 4, 13, 33, and 50 wk old) compared with human idiopathic dilated cardiomyopathy data; and 3) microRNA expression, with rat microRNA microarrays in left ventricles of 2-day-old HHR and age-matched NHR. We also investigated experimentally validated microRNA-mRNA interactions. Whole-genome sequencing revealed unique variants mostly located in noncoding regions of HHR and NHR. We found 29 genes differentially expressed in at least 1 age. Genes encoding desmoglein 2 (Dsg2) and transthyretin (Ttr) were significantly differentially expressed at all ages in the HHR, but only Ttr was also differentially expressed in human idiopathic cardiomyopathy. Lastly, only two microRNAs differentially expressed in the HHR were present in our comparison of validated microRNA-mRNA interactions. These two microRNAs interact with five of the genes studied. Our study shows that genes involved in monogenic forms of human cardiomyopathies may also influence polygenic forms of the disease.
- Authors: Prestes, Priscilla , Marques, Francine , Lopez-Campos, Guillermo , Lewandowski, Paul , Delbridge, Lea , Charchar, Fadi , Harrap, Stephen
- Date: 2018
- Type: Text , Journal article
- Relation: Physiological Genomics Vol. 50, no. 9 (2018), p. 680-687
- Full Text:
- Reviewed:
- Description: Hypertrophic cardiomyopathy thickens heart muscles, reducing functionality and increasing risk of cardiac disease and morbidity. Genetic factors are involved, but their contribution is poorly understood. We used the hypertrophic heart rat (HHR), a unique normotensive polygenic model of cardiac hypertrophy and heart failure, to investigate the role of genes associated with monogenic human cardiomyopathy. We selected 42 genes involved in monogenic human cardiomyopathies to study: 1) DNA variants, by sequencing the whole genome of 13-wk-old HHR and age-matched normal heart rat (NHR), its genetic control strain; 2) mRNA expression, by targeted RNA-sequencing in left ventricles of HHR and NHR at 5 ages (2 days old and 4, 13, 33, and 50 wk old) compared with human idiopathic dilated cardiomyopathy data; and 3) microRNA expression, with rat microRNA microarrays in left ventricles of 2-day-old HHR and age-matched NHR. We also investigated experimentally validated microRNA-mRNA interactions. Whole-genome sequencing revealed unique variants mostly located in noncoding regions of HHR and NHR. We found 29 genes differentially expressed in at least 1 age. Genes encoding desmoglein 2 (Dsg2) and transthyretin (Ttr) were significantly differentially expressed at all ages in the HHR, but only Ttr was also differentially expressed in human idiopathic cardiomyopathy. Lastly, only two microRNAs differentially expressed in the HHR were present in our comparison of validated microRNA-mRNA interactions. These two microRNAs interact with five of the genes studied. Our study shows that genes involved in monogenic forms of human cardiomyopathies may also influence polygenic forms of the disease.
Cardiac telomere length in heart development, function, and disease
- Booth, Scott, Charchar, Fadi
- Authors: Booth, Scott , Charchar, Fadi
- Date: 2017
- Type: Text , Journal article , Review
- Relation: Physiological Genomics Vol. 49, no. 7 (2017), p. 368-384
- Relation: http://purl.org/au-research/grants/nhmrc/1034371
- Full Text: false
- Reviewed:
- Description: Telomeres are repetitive nucleoprotein structures at chromosome ends, and a decrease in the number of these repeats, known as a reduction in telomere length (TL), triggers cellular senescence and apoptosis. Heart disease, the worldwide leading cause of death, often results from the loss of cardiac cells, which could be explained by decreases in TL. Due to the cell-specific regulation of TL, this review focuses on studies that have measured telomeres in heart cells and critically assesses the relationship between cardiac TL and heart function. There are several lines of evidence that have identified rapid changes in cardiac TL during the onset and progression of heart disease as well as at critical stages of development. There are also many factors, such as the loss of telomeric proteins, oxidative stress, and hypoxia, that decrease cardiac TL and heart function. In contrast, antioxidants, calorie restriction, and exercise can prevent both cardiac telomere attrition and the progression of heart disease. TL in the heart is also indicative of proliferative potential and could facilitate the identification of cells suitable for cardiac rejuvenation. Although these findings highlight the involvement of TL in heart function, there are important questions regarding the validity of animal models, as well as several confounding factors, that need to be considered when interpreting results and planning future research. With these in mind, elucidating the telomeric mechanisms involved in heart development and the transition to disease holds promise to prevent cardiac dysfunction and potentiate regeneration after injury. © 2017 the American Physiological Society.
Telomere dynamics during aging in polygenic left ventricular hypertrophy
- Marques, Francine, Booth, Scott, Prestes, Priscilla, Curl, Claire, Delbridge, Lea, Lewandowski, Paul, Harrap, Stephen, Charchar, Fadi
- Authors: Marques, Francine , Booth, Scott , Prestes, Priscilla , Curl, Claire , Delbridge, Lea , Lewandowski, Paul , Harrap, Stephen , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article
- Relation: Physiological Genomics Vol. 48, no. 1 (2016), p. 42-49
- Full Text:
- Reviewed:
- Description: Short telomeres are associated with increased risk of cardiovascular disease. Here we studied cardiomyocyte telomere length at key ages during the ontogeny of cardiac hypertrophy and failure in the hypertrophic heart rat (HHR) and compared these with the normal heart rat (NHR) control strain. Key ages corresponded with the pathophysiological sequence beginning with fewer cardiomyocytes (2 days), leading to left ventricular hypertrophy (LVH) (13 wk) and subsequently progression to heart failure (38 wk). We measured telomere length, tissue activity of telomerase, mRNA levels of telomerase reverse transcriptase (Tert) and telomerase RNA component (Terc), and expression of the telomeric regulator microRNA miR-34a. Cardiac telomere length was longer in the HHR compared with the control strain at 2 days and 38 wk, but shorter at 13 wk. Neonatal HHR had higher cardiac telomerase activity and expression of Tert and miR-34a. Telomerase activity was not different at 13 or 38 wk. Tert mRNA and Terc RNA were overexpressed at 38 wk, while miR-34a was overexpressed at 13 wk but downregulated at 38 wk. Circulating leukocytes were strongly correlated with cardiac telomere length in the HHR only. The longer neonatal telomeres in HHR are likely to reflect fewer fetal and early postnatal cardiomyocyte cell divisions and explain the reduced total cardiomyocyte complement that predisposes to later hypertrophy and failure. Although shorter telomeres were a feature of cardiac hypertrophy at 13 wk, they were not present at the progression to heart failure at 38 wk. © 2016 the American Physiological Society.
- Authors: Marques, Francine , Booth, Scott , Prestes, Priscilla , Curl, Claire , Delbridge, Lea , Lewandowski, Paul , Harrap, Stephen , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article
- Relation: Physiological Genomics Vol. 48, no. 1 (2016), p. 42-49
- Full Text:
- Reviewed:
- Description: Short telomeres are associated with increased risk of cardiovascular disease. Here we studied cardiomyocyte telomere length at key ages during the ontogeny of cardiac hypertrophy and failure in the hypertrophic heart rat (HHR) and compared these with the normal heart rat (NHR) control strain. Key ages corresponded with the pathophysiological sequence beginning with fewer cardiomyocytes (2 days), leading to left ventricular hypertrophy (LVH) (13 wk) and subsequently progression to heart failure (38 wk). We measured telomere length, tissue activity of telomerase, mRNA levels of telomerase reverse transcriptase (Tert) and telomerase RNA component (Terc), and expression of the telomeric regulator microRNA miR-34a. Cardiac telomere length was longer in the HHR compared with the control strain at 2 days and 38 wk, but shorter at 13 wk. Neonatal HHR had higher cardiac telomerase activity and expression of Tert and miR-34a. Telomerase activity was not different at 13 or 38 wk. Tert mRNA and Terc RNA were overexpressed at 38 wk, while miR-34a was overexpressed at 13 wk but downregulated at 38 wk. Circulating leukocytes were strongly correlated with cardiac telomere length in the HHR only. The longer neonatal telomeres in HHR are likely to reflect fewer fetal and early postnatal cardiomyocyte cell divisions and explain the reduced total cardiomyocyte complement that predisposes to later hypertrophy and failure. Although shorter telomeres were a feature of cardiac hypertrophy at 13 wk, they were not present at the progression to heart failure at 38 wk. © 2016 the American Physiological Society.
Changes in the leukocyte methylome and its effect on cardiovascular-related genes after exercise
- Denham, Joshua, O'Brien, Brendan, Marques, Francine, Charchar, Fadi
- Authors: Denham, Joshua , O'Brien, Brendan , Marques, Francine , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Journal of Applied Physiology Vol. 118, no. 4 (2015), p. 475-488
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text: false
- Reviewed:
- Description: Physical exercise has proven cardiovascular benefits, yet there is no clear understanding of the related molecular mechanisms leading to this. Here we determined the beneficial epigenetic effects of exercise after sprint interval training, a form of exercise known to improve cardiometabolic health. We quantified genome-wide leukocyte DNA methylation of 12 healthy young (18-24 yr) men before and after 4 wk (thrice weekly) of sprint interval training using the 450K BeadChip (Illumina) and validated gene expression changes in an extra seven subjects. Exercise increased subjects' cardiorespiratory fitness and maximal running performance, and decreased low-density lipoprotein cholesterol concentration in conjunction with genome-wide DNA methylation changes. Notably, many CpG island and gene promoter regions were demethylated after exercise, indicating increased genome-wide transcriptional changes. Among genes with DNA methylation changes, epidermal growth factor (EGF), a ligand of the epidermal growth factor receptor known to be involved in cardiovascular disease, was demethylated and showed decreased mRNA expression. Additionally, we found that in microRNAs miR-21 and miR-210, gene DNA methylation was altered by exercise causing a cascade effect on the expression of the mature microRNA involved in cardiovascular function. Our findings demonstrate that exercise alters DNA methylation in circulating blood cells in microRNA and protein-coding genes associated with cardiovascular physiology. Copyright © 2015 the American Physiological Society
Contribution of microRNA to pathological fibrosis in cardiorenal syndrome : Impact of uremic toxins
- Rana, Indrajeetsinh, Kompa, Andrew, Skommer, Joanna, Wang, Bing, Lekawanvijit, Suree, Kelly, Darren, Krum, Henry, Charchar, Fadi
- Authors: Rana, Indrajeetsinh , Kompa, Andrew , Skommer, Joanna , Wang, Bing , Lekawanvijit, Suree , Kelly, Darren , Krum, Henry , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Physiological Reports Vol. 3, no. 4 (2015), p. 1-15
- Full Text:
- Reviewed:
- Description: Progressive reduction in kidney function in patients following myocardial infarction (MI) is associated with an increase in circulating uremic toxins levels leading to increased extracellular matrix deposition. We have recently reported that treatment with uremic toxin adsorbent AST-120 in rats with MI inhibits serum levels of uremic toxin indoxyl sulfate (IS) and downregulates expression of cardiac profibrotic cytokine transforming growth factor beta (TGF-β1). In this study, we examined the effect of uremic toxins post-MI on cardiac microRNA-21 and microRNA-29b expression, and also the regulation of target genes and matrix remodeling proteins involved in TGFβ1 and angiotensin II signaling pathways. Sixteen weeks after MI, cardiac tissues were assessed for pathological and molecular changes. The percentage area of cardiac fibrosis was 4.67 ± 0.17 in vehicle-treated MI, 2.9 ± 0.26 in sham, and 3.32 ± 0.38 in AST-120-treated MI, group of rats. Compared to sham group, we found a twofold increase in the cardiac expression of microRNA-21 and 0.5-fold decrease in microRNA-29b in heart tissue from vehicle-treated MI. Treatment with AST-120 lowered serum IS levels and attenuated both, cardiac fibrosis and changes in expression of these microRNAs observed after MI. We also found increased mRNA expression of angiotensin-converting enzyme (ACE) and angiotensin receptor 1a (Agtr1a) in cardiac tissue collected from MI rats. Treatment with AST-120 attenuated both, expression of ACE and Agtr1a mRNA. Exposure of rat cardiac fibroblasts to IS upregulated angiotensin II signaling and altered the expression of both microRNA-21 and micro- RNA-29b. These results collectively suggest a clear role of IS in altering microRNA-21 and microRNA-29b in MI heart, via a mechanism involving angiotensin signaling pathway, which leads to cardiac fibrosis. © 2015 The Authors.
- Authors: Rana, Indrajeetsinh , Kompa, Andrew , Skommer, Joanna , Wang, Bing , Lekawanvijit, Suree , Kelly, Darren , Krum, Henry , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Physiological Reports Vol. 3, no. 4 (2015), p. 1-15
- Full Text:
- Reviewed:
- Description: Progressive reduction in kidney function in patients following myocardial infarction (MI) is associated with an increase in circulating uremic toxins levels leading to increased extracellular matrix deposition. We have recently reported that treatment with uremic toxin adsorbent AST-120 in rats with MI inhibits serum levels of uremic toxin indoxyl sulfate (IS) and downregulates expression of cardiac profibrotic cytokine transforming growth factor beta (TGF-β1). In this study, we examined the effect of uremic toxins post-MI on cardiac microRNA-21 and microRNA-29b expression, and also the regulation of target genes and matrix remodeling proteins involved in TGFβ1 and angiotensin II signaling pathways. Sixteen weeks after MI, cardiac tissues were assessed for pathological and molecular changes. The percentage area of cardiac fibrosis was 4.67 ± 0.17 in vehicle-treated MI, 2.9 ± 0.26 in sham, and 3.32 ± 0.38 in AST-120-treated MI, group of rats. Compared to sham group, we found a twofold increase in the cardiac expression of microRNA-21 and 0.5-fold decrease in microRNA-29b in heart tissue from vehicle-treated MI. Treatment with AST-120 lowered serum IS levels and attenuated both, cardiac fibrosis and changes in expression of these microRNAs observed after MI. We also found increased mRNA expression of angiotensin-converting enzyme (ACE) and angiotensin receptor 1a (Agtr1a) in cardiac tissue collected from MI rats. Treatment with AST-120 attenuated both, expression of ACE and Agtr1a mRNA. Exposure of rat cardiac fibroblasts to IS upregulated angiotensin II signaling and altered the expression of both microRNA-21 and micro- RNA-29b. These results collectively suggest a clear role of IS in altering microRNA-21 and microRNA-29b in MI heart, via a mechanism involving angiotensin signaling pathway, which leads to cardiac fibrosis. © 2015 The Authors.
Increased expression of telomere-regulating genes in endurance athletes with long leukocyte telomeres
- Denham, Joshua, O'Brien, Brendan, Prestes, Priscilla, Brown, Nicholas, Charchar, Fadi
- Authors: Denham, Joshua , O'Brien, Brendan , Prestes, Priscilla , Brown, Nicholas , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Journal of Applied Physiology Vol. 120, no. 2 (2015), p. 148-158
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: Leukocyte telomeres shorten with age, and excessive shortening is associated with age-related cardiometabolic diseases. Exercise training may prevent disease through telomere length maintenance although the optimal amount of exercise that attenuates telomere attrition is unknown. Furthermore, the underlying molecular mechanisms responsible for the enhanced telomere maintenance observed in endurance athletes is poorly understood. We quantified the leukocyte telomere length and analyzed the expression of telomere-regulating genes in endurance athletes and healthy controls (both n = 61), using quantitative PCR. We found endurance athletes have significantly longer (7.1%, 208-416 nt) leukocyte telomeres and upregulated TERT (2.0-fold) and TPP1 (1.3-fold) mRNA expression compared with controls in age-adjusted analysis. The telomere length and telomere-regulating gene expression differences were no longer statistically significant after adjustment for resting heart rate and relative (V) over dotO(2 max) (all P > 0.05). Resting heart rate emerged as an independent predictor of leukocyte telomere length and TERT and TPP1 mRNA expression in stepwise regression models. To gauge whether volume of exercise was associated with leukocyte telomere length, we divided subjects into running and cycling tertiles (distance covered per week) and found individuals in the middle and highest tertiles had longer telomeres than individuals in the lowest tertile. These data emphasize the importance of cardiorespiratory fitness and exercise training in the prevention of biological aging. They also support the concept that moderate amounts of exercise training protects against biological aging, while higher amounts may not elicit additional benefits.
- Authors: Denham, Joshua , O'Brien, Brendan , Prestes, Priscilla , Brown, Nicholas , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Journal of Applied Physiology Vol. 120, no. 2 (2015), p. 148-158
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: Leukocyte telomeres shorten with age, and excessive shortening is associated with age-related cardiometabolic diseases. Exercise training may prevent disease through telomere length maintenance although the optimal amount of exercise that attenuates telomere attrition is unknown. Furthermore, the underlying molecular mechanisms responsible for the enhanced telomere maintenance observed in endurance athletes is poorly understood. We quantified the leukocyte telomere length and analyzed the expression of telomere-regulating genes in endurance athletes and healthy controls (both n = 61), using quantitative PCR. We found endurance athletes have significantly longer (7.1%, 208-416 nt) leukocyte telomeres and upregulated TERT (2.0-fold) and TPP1 (1.3-fold) mRNA expression compared with controls in age-adjusted analysis. The telomere length and telomere-regulating gene expression differences were no longer statistically significant after adjustment for resting heart rate and relative (V) over dotO(2 max) (all P > 0.05). Resting heart rate emerged as an independent predictor of leukocyte telomere length and TERT and TPP1 mRNA expression in stepwise regression models. To gauge whether volume of exercise was associated with leukocyte telomere length, we divided subjects into running and cycling tertiles (distance covered per week) and found individuals in the middle and highest tertiles had longer telomeres than individuals in the lowest tertile. These data emphasize the importance of cardiorespiratory fitness and exercise training in the prevention of biological aging. They also support the concept that moderate amounts of exercise training protects against biological aging, while higher amounts may not elicit additional benefits.
- Rana, Indrajeetsinh, Velkoska, Elena, Patel, Sheila, Burrell, Louise, Charchar, Fadi
- Authors: Rana, Indrajeetsinh , Velkoska, Elena , Patel, Sheila , Burrell, Louise , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: American Journal of Physiology - Renal Physiology Vol. 309, no. 11 (2015), p. F943-F954
- Full Text: false
- Reviewed:
- Description: Cardiovascular disease, including cardiac hypertrophy, is common in patients with kidney disease and can be partially attenuated using blockers of the renin-angiotensin system (RAS). It is unknown whether cardiac microRNAs contribute to the pathogenesis of cardiac hypertrophy or to the protective effect of RAS blockade in kidney disease. Using a subtotal nephrectomy rat model of kidney injury, we investigated changes in cardiac microRNAs that are known to have direct target genes involved in the regulation of apoptosis, fibrosis, and hypertrophy. The effect of treatment with the angiotensin-converting enzyme (ACE) inhibitor ramipril on cardiac microRNAs was also investigated. Kidney injury led to a significant increase in cardiac microRNA-212 and mi- croRNA-132 expression. Ramipril reduced cardiac hypertrophy, attenuated the increase in microRNA-212 and microRNA-132, and significantly increased microRNA-133 and microRNA-1 expression. There was altered expression of caspase-9, B cell lymphoma-2, transforming growth factor-β, fibronectin 1, collagen type 1A1, and forkhead box protein O3, which are all known to be involved in the regulation of apoptosis, fibrosis, and hypertrophy in cardiac cells while being targets for the above microRNAs. ACE inhibitor treatment increased expression of microRNA-133 and microRNA-1. The inhibitory action of ACE inhibitor treatment on increased cardiac NADPH oxidase isoform 1 expression after subtotal nephrectomy surgery suggests that inhibition of oxidative stress is also one of mechanism of ACE inhibitor-mediated cardioprotection. These finding suggests the involvement of microRNAs in the cardioprotective action of ACE inhibition in acute renal injury, which is mediated through an inhibitory action on profibrotic and proapoptotic target genes and stimulatory action on antihypertrophic and antiapoptotic target genes. © 2015 the American Physiological Society. Funding: APP1048285; NHMRC; National Health and Medical Research Council
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