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  • In conjunction with decreased mean

    2019-07-06

    In conjunction with decreased mean shortening velocity, vertebrate cardiac aging is characterized by a prolongation of systolic contraction time [8,[50], [51], [52]]. The Drosophila heart similarly displays increasingly longer systolic intervals with advancing age [23,44]. The mechanistic basis of these changes likely involves variations in, and modifications to, several conserved cardiomyocyte calcium handling components across species. In mammals, various studies have documented coordinated changes in protein function and/or gene expression with aging that prolong the calcium transient that drives myocardial contraction [8,52,53]. Upon membrane depolarization, calcium enters the cardiomyocyte through L-type calcium channels, prompting the release of additional calcium from the sarcoplasmic reticulum (SR), the cardiomyocyte's intracellular storage compartment. Although L-type calcium channel density is not apparently affected by age, its function seems to decline, as illustrated by a reduction in the calcium transient amplitude and slower channel inactivation [8,41,54,55]. Moreover, the rate of calcium reuptake into the SR decreases in senescent myocardium [48,53,56,57]. An age-associated reduction in the transcription of SERCA2, the gene that encodes the SR calcium pump, accounts in part for decreased SR pump site density and the impaired sequestration of intracellular calcium [48,55,58]. However, expression of the Na+/Ca2+ exchanger, which extrudes intracellular calcium from the cell, increases between adulthood and senescence, and enhanced antiporter-mediated flux may partially compensate for impaired calcium reuptake into the SR [48]. The calcium cycling properties of the Drosophila cardiac tube are also negatively impacted by age. Old flies display altered intracellular cardiomyocyte calcium dynamics, with a prolonged transient decay, which promotes the extended periods of systole observed in senescent animals [23,44,59]. Recently, whole-cell patch clamp recordings of calcium currents across the membrane of isolated Drosophila cardiomyocytes confirmed the 168682-53-9 possess a conserved compendium of L- and T-type calcium channels [60]. As in mammals, L-type (A1D in Drosophila) channels in flies serve as the main conduits for sarcolemmal calcium flux. These channels share regulatory properties, such as calcium dependent inactivation, a critical negative feedback process that modulates the rate of channel inactivation, with their vertebrate counterparts. While not studied directly, these properties may analogously deteriorate with age, slow inactivation, and extend contraction. Furthermore, microarray data reveal that the expression of genes involved with calcium handling, including both L- and T-type channels, the ryanodine receptor, SERCA, and the Na+/Ca2+ exchanger, is significantly reduced over time [15,24], which could further engender altered calcium transients in aged fly cardiomyocytes. Importantly, cardiac arrhythmias are a byproduct of aberrant calcium handling, and their incidence increases in both elderly humans and flies [8,23,44,61]. Diminished adrenergic signaling and autonomic modulation of cardiac function is an important factor in mammalian age-associated cardiovascular change [8,48,62]. For example, the ability of β-adrenergic receptor stimulation to increase contractility declines over time. This results from a failure of β-adrenergic receptor stimulation to augment the intracellular calcium transient to the same extent in cardiomyocytes from senescent hearts relative to those from younger hearts [48,63]. The observed age-related reduction in β-adrenergic receptor modulation of cardiac contraction is attributable, at least in part, to insufficient enhancement of the activity of L-type calcium channels [48,63]. The root cause of these changes is not completely understood, but several lines of evidence indicate reduced myocardial β-adrenergic receptor density, their functional decline, and deficits in the β-adrenergic signaling cascade with advanced age [48,64,65]. Interestingly, Drosophila express components homologous to those of the vertebrate pathway, including adrenergic-like octopamine receptors (OctαRs, and OctβRs), adenylyl cyclase (rutabaga), phosphodiesterase (dunce), and both regulatory and catalytic subunits of protein kinase A (PKA), and their cardiac L-type calcium channels exhibit PKA-mediated current enhancement [60]. The expression of all aforementioned genes uniformly declines with age in Drosophila cardiomyocytes [15,24,66], suggesting old fly hearts may also exhibit blunted responses to adrenergic stimulation.