Abstract 371: Down Regulation of ECM Genes Laminin and Collagen IV Lead to Preserved Cardiac Function With Age and Increased Lifespan in Drosophila
Increased deposition of extracellular matrix (ECM) is observed in all advanced age heart failure patients, but current model systems are complex and slow to age. To investigate the effect of extracellular remodeling on mechanical function in genetically tractable, rapidly aging, and simple model organisms, we employed Drosophila melanogaster, which has a simple trilayered heart tube.
We found that two common wildtype strains of Drosophila, i.e. yellow-white (yw) and white-1118 (w1118), exhibit different cytoskeletal and ECM remodeling with age. Using a recently developed nanoindentation method to measure cardiomyocyte stiffness and high speed optical imaging to assess contractility of intact Drosophila hearts, we found that yw flies had stiffer intercalated discs (ICD) and exhibited diastolic dysfunction with age. On the other hand, w1118 flies had a shorter lifespan compared to yw, did not exhibit ICD stiffening, had a less severe diastolic dysfunction, and showed an increase in ECM layer thickness between ventral muscle (VM) and cardiomyocyte (CM) layers of the heart tube. To modulate ECM and assess its effect in the aged w1118 flies, we knocked-down ECM genes LamininA and Viking (homologous to Collagen IV). Both ECM KD genotypes exhibited diastolic dilation with increased fractional shortening at adult (1wk) and aged (5wk) time points. The LamininA KD resulted in decreased cardiomyocyte stiffness correlating with increased relaxation velocities in adult flies and preservation of shortening and relaxation velocities in aged flies over controls. However, both the LamininA and Collagen IV KD flies experienced a basal increase in the decoupling of their cardiomyocytes as determined by heart period variance and % fibrillar heart-beats. These conductance issues were not enough to counteract the increased cardiac output and performance with age, and the Collagen IV KD outlived controls by 1.5 weeks median survival and the LamininA KD by 3 weeks. This suggests that the cell-ECM contacts in the basement membrane are intimately tied not only to the coupling of the cardiomyocytes of the Drosophila heart tube but also to cytoskeletal remodeling, but perhaps different ECM proteins have different mechanisms for interacting with the cardiomyocyte cytoskeleton.
Author Disclosures: A.O. Sessions: None.
- © 2015 by American Heart Association, Inc.