Conditional mutations in SERCA, the Sarco-endoplasmic reticulum Ca2+-ATPase, alter heart rate and rhythmicity in Drosophila

Sanyal, Subhabrata; Jennings, Tricia; Dowse, Harold B.; Ramaswami, Mani

doi:10.1007/s00360-005-0046-7

Cited by 48 publications

(52 citation statements)

References 59 publications

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“…1). This is in line with previous measurements that range between 2.4 Hz and 4.5 Hz (Alex et al, 2015;Gu and Singh, 1995;Sanyal et al, 2006;Sénatore et al, 2010;Sláma and Farkaš, 2005). Several parameters influence heartbeat rate, i.e.…”

Section: Intracardiac Valve Cells -Mode Of Operationsupporting

confidence: 93%

Formation and function of intracardiac valve cells in the Drosophila heart

Lammers

Abeln

Hüsken

et al. 2017

Journal of Experimental Biology

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Drosophila harbours a simple tubular heart that ensures haemolymph circulation within the body. The heart is built by a few different cell types, including cardiomyocytes that define the luminal heart channel and ostia cells that constitute openings in the heart wall allowing haemolymph to enter the heart chamber. Regulation of flow directionality within a tube, such as blood flow in arteries or insect haemolymph within the heart lumen, requires a dedicated gate, valve or flap-like structure that prevents backflow of fluids. In the Drosophila heart, intracardiac valves provide this directionality of haemolymph streaming, with one valve being present in larvae and three valves in the adult fly. Each valve is built by two specialised cardiomyocytes that exhibit a unique histology. We found that the capacity to open and close the heart lumen relies on a unique myofibrillar setting as well as on the presence of large membranous vesicles. These vesicles are of endocytic origin and probably represent unique organelles of valve cells. Moreover, we characterised the working mode of the cells in real time. Valve cells exhibit a highly flexible shape and, during each heartbeat, oscillating shape changes result in closing and opening of the heart channel. Finally, we identified a set of novel valve cell markers useful for future in-depth analyses of cell differentiation in wild-type and mutant animals.

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Section: Intracardiac Valve Cells -Mode Of Operationsupporting

confidence: 93%

Formation and function of intracardiac valve cells in the Drosophila heart

Lammers

Abeln

Hüsken

et al. 2017

Journal of Experimental Biology

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“…Yet, a similar connection has been described for a conditionally mutant SERCA form in Drosophila (49). Sanyal et al (49) found HR strikingly reduced when SERCA activity was inactivated. In addition, Rubio et al (47) also demonstrated the involvement of augmented Ca 2ϩ cycling in arrhythmogenesis after overexpression of SERCA1 in a L-type voltage-dependent calcium channel-overexpressing transgenic mouse model.…”

Section: Discussionmentioning

confidence: 99%

Limited functional and metabolic improvements in hypertrophic and healthy rat heart overexpressing the skeletal muscle isoform of SERCA1 by adenoviral gene transfer in vivo

O’Donnell

Fields²,

Xu³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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O'Donnell JM, Fields A, Xu X, Chowdhury SA, Geenen DL, Bi J. Limited functional and metabolic improvements in hypertrophic and healthy rat heart overexpressing the skeletal muscle isoform of SERCA1 by adenoviral gene transfer in vivo. Am J Physiol Heart Circ Physiol 295: H2483-H2494, 2008. First published October 24, 2008 doi:10.1152/ajpheart.01023.2008.-Adenoviral gene transfer of sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA)2a to the hypertrophic heart in vivo has been consistently reported to lead to enhanced myocardial contractility. It is unknown if the faster skeletal muscle isoform, SERCA1, expressed in the whole heart in early failure, leads to similar improvements and whether metabolic requirements are maintained during an adrenergic challenge. In this study, Ad.cmv.SERCA1 was delivered in vivo to aortic banded and shamoperated Sprague-Dawley rat hearts. The total SERCA content increased 34%. At 48 -72 h posttransfer, echocardiograms were acquired, hearts were excised and retrograded perfused, and hemodynamics were measured parallel to NMR measures of the phosphocreatine (PCr)-to-ATP ratio (PCr/ATP) and energy substrate selection at basal and high workloads (isoproterenol). In the Langendorff mode, the rate-pressure product was enhanced 27% with SERCA1 in hypertrophic hearts and 10% in shams. The adrenergic response to isoproterenol was significantly potentiated in both groups with SERCA1.31 P NMR analysis of PCr/ATP revealed that the ratio remained low in the hypertrophic group with SERCA1 overexpression and was not further compromised with adrenergic challenge.13 C NMR analysis revealed fat and carbohydrate oxidation were unaffected at basal with SERCA1 expression; however, there was a shift from fats to carbohydrates at higher workloads with SERCA1 in both groups. Transport of NADH-reducing equivalents into the mitochondria via the ␣-ketoglutamate-malate transporter was not affected by either SERCA1 overexpression or adrenergic challenge in both groups. Echocardiograms revealed an important distinction between in vivo versus ex vivo data. In contrast to previous SERCA2a studies, the echocardiogram data revealed that SERCA1 expression compromised function (fractional shortening) in the hypertrophic group. Shams were unaffected. While our ex vivo findings support much of the earlier cardiomyocyte and transgenic data, the in vivo data challenge previous reports of improved cardiac function in heart failure models after SERCA intervention. sarco(endo)plasmic reticulum Ca 2ϩ -ATPase; glucose oxidation; fatty acid oxidation; phosphocreatine-to-ATP ratio; myocardial energy potential THE CHANGES in intracellular Ca 2ϩ handling reported for the failing myocardium have been linked to sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA). Calcium uptake into the sarcoplasmic reticulum (SR) by SERCA determines the rate of calcium removal for relaxation, the SR calcium content, and calcium released for contractions (33,45). In the failing heart, it has been proposed that SERCA contributes to reduced contractil...

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“…More recently, the Drosophila model has also been adopted to investigate cardiac physiology, performance and aging Sanyal et al, 2006;Wolf et al, 2006;Ocorr et al, 2007;Mery et al, 2008) using assays to determine the contractility, rhythmicity and other performance parameters, for example, stress assay, in which the cardiac performance is tested by using external electrical pacing of the heart rate (Paternostro et al, 2001;, ultrasound-like image analysis of the heart in intact flies [using optical coherence tomography (OCT); Wolf et al, 2006], digital high-speed video imaging of semi-intact adult fly heart, which in addition allows characterizing the contractility and rhythmicity of the heart (Ocorr et al, 2007). Using these assays, it was found that the fly homologue of the KCNQ1 potassium channel gene, which is associated with human cardiac arrhythmias and long QT, causes heart rhythm abnormalities also when mutated in flies, and they become more severe with age (Ocorr et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Dystrophin deficiency in Drosophila reduces lifespan and causes a dilated cardiomyopathy phenotype

et al. 2008

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SummaryA number of studies have been conducted recently on the model organism Drosophila to determine the function of genes involved in human disease, including those implicated in neurological disorders, cancer and metabolic and cardiovascular diseases. The simple structure and physiology of the Drosophila heart tube together with the available genetics provide a suitable in vivo assay system for studying cardiac gene functions. In our study, we focus on analysis of the role of dystrophin (Dys) in heart physiology. As in humans, the Drosophila dys gene encodes multiple isoforms, of which the large isoforms ( DLPs ) and a truncated form ( Dp117 ) are expressed in the adult heart. Here, we show that the loss of dys function in the heart leads to an age-dependent disruption of the myofibrillar organization within the myocardium as well as to alterations in cardiac performance. dys RNAi-mediated knockdown in the mesoderm also shortens lifespan. Knockdown of all or deletion of the large isoforms increases the heart rate by shortening the diastolic intervals (relaxation phase) of the cardiac cycle. Morphologically, loss of the large DLPs isoforms causes a widening of the cardiac tube and a lower fractional shortening, a phenotype reminiscent of dilated cardiomyopathy. The dilated dys mutant phenotype was reversed by expressing a truncated mammalian form of dys ( Dp116 ). Our results illustrate the utility of Drosophila as a model system to study dilated cardiomyopathy and other muscular-dystrophy-associated phenotypes.

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Conditional mutations in SERCA, the Sarco-endoplasmic reticulum Ca2+-ATPase, alter heart rate and rhythmicity in Drosophila

Cited by 48 publications

References 59 publications

Formation and function of intracardiac valve cells in the Drosophila heart

Formation and function of intracardiac valve cells in the Drosophila heart

Limited functional and metabolic improvements in hypertrophic and healthy rat heart overexpressing the skeletal muscle isoform of SERCA1 by adenoviral gene transfer in vivo

Dystrophin deficiency in Drosophila reduces lifespan and causes a dilated cardiomyopathy phenotype

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