Abstract
Abnormal sarcoendoplasmic reticulum Calcium ATPase (SERCA) function has been associated with poor cardiac function in humans. While modifiers of SERCA function have been identified and studied using animal models, further investigation has been limited by the absence of a model system that is amenable to large-scale genetic screens. Drosophila melanogaster is an ideal model system for the investigation of SERCA function due to the significant homology to human SERCA and the availability of versatile genetic screening tools. To further the use of Drosophila as a model for examining the role of SERCA in cardiac function, we examined cardiac function in adult flies. Using optical coherence tomography (OCT) imaging in awake, adult Drosophila, we have been able to characterize cardiac chamber dimensions in flies with disrupted in Drosophila SERCA (CaP60A). We found that the best studied CaP60A mutant, the conditional paralytic mutant CaP60Akum170, develops marked bradycardia and chamber enlargement that is closely linked to the onset of paralysis and dependent on extra cardiac CaP60A. In contrast to prior work, we show that disruption of CaP60A in a cardiac specific manner results in cardiac dilation and dysfunction rather than alteration in heart rate. In addition, the co-expression of a calcium release channel mutation with CaP60A kum170 is sufficient to rescue the cardiac phenotype but not paralysis. Finally, we show that CaP60A overexpression is able to rescue cardiac function in a model of Drosophila cardiac dysfunction similar to what is observed in mammals. Thus, we present a cardiac phenotype associated with Drosophila SERCA dysfunction that would serve as additional phenotyping for further large-scale genetic screens for novel modifiers of SERCA function.
Highlights
Derangements in calcium handling have been implicated as common pathway in cardiac dysfunction
Previous work suggested that sarcoendoplasmic reticulum ATPase pump (SERCA) primarily maintains heart rate in Drosophila [11,13], a finding that differs from the observed function of SERCA in the mammalian heart to maintain normal contractile function [22] and may be due to limitations of the techniques to measure adult Drosophila cardiac function
We examined the effect of varying duration of heat shock on both paralysis and cardiac function
Summary
Derangements in calcium handling have been implicated as common pathway in cardiac dysfunction. A major regulator of myocyte calcium homeostasis is the sarcoendoplasmic reticulum ATPase pump (SERCA), which is responsible for removing a significant fraction of calcium from the cytosol into the sarcoplasmic reticulum after cardiac contraction [1]. Each cardiac contraction represents the coordinated action of calcium into and removal out of the cytosol. Perturbations in this finely coordinated mechanism, such as in altered SERCA function, can lead to cell and, organ dysfunction over time [2]. Regulators of SERCA function in mammals, such as phospholamban [3] and sarcolipin [4], have been examined as potential therapeutic targets. Whether additional modifiers of SERCA function exist in mammals is unknown
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