Conserved Chamber-Specific Polyploidy Maintains Heart Function inDrosophila

Abstract

Developmentally programmed polyploidy (whole-genome-duplication) of cardiomyocytes is common across evolution. Functions of such polyploidy are essentially unknown. Here, we reveal roles for precise polyploidy levels in cardiac tissue. We highlight a conserved asymmetry in polyploidy level between cardiac chambers in Drosophila larvae and humans. In Drosophila, differential Insulin Receptor (InR)sensitivity leads the heart chamber to reach a higher ploidy/cell size relative to the aorta chamber. Cardiac ploidy-reduced animals exhibit reduced heart chamber size, stroke volume, cardiac output, and acceleration of circulating hemocytes. These Drosophila phenotypes mimic systemic human heart failure. Using human donor hearts, we reveal asymmetry in nuclear volume (ploidy) and insulin signaling between the left ventricle and atrium. Our results identify productive and likely conserved roles for polyploidy in cardiac chambers and suggest precise ploidy levels sculpt many developing tissues. These findings of productive cardiomyocyte polyploidy impact efforts to block developmental polyploidy to improve heart injury recovery.

Anciently duplicated genes continuously recruited to heart expression in vertebrate evolution are associated with heart chamber increase

“…Functional enrichment analyses of human genes based on Database for Annotation, Visualization and Integrated Discovery (DAVID) Bioinformatics Resources (Huang et al, 2009a, 2009b) show that they are enriched in many processes involved in cardiac muscle organization and contraction, such as dilated cardiomyopathy, cardiac muscle contraction, cyclase‐related activities, contractile fiber, and myofibril (Figure 3a). Recent research in humans has reported that transcriptional differences between atrial and ventricular cardiomyocyte populations suggest distinct developmental origins, unique hemodynamic influences, and specialized functions within cardiac chambers (Chakraborty et al, 2023). Additionally, cardiomyocytes are more prevalent in ventricles compared to atria, indicating a higher proportion of these cells in the ventricular region (Litviňuková et al, 2020; Tucker et al, 2020).…”

An unscheduled switch to endocycles induces a reversible senescent arrest that impairs growth of theDrosophilawing disc

“…After more significant tissue loss, an increase in iEC size can also regenerate tissue mass in a process called compensatory cellular hypertrophy (CCH). 1,5,7,10,[13][14][15][16][17][18] In contrast, other evidence indicates that in some contexts polyploidy can restrict regeneration. 1,5,[19][20][21][22][23][24] Recently, there has been an intense interest in the contribution of iECs to cancer therapy resistance and cancer relapse.…”