Identifying the Molecular Mechanisms of Diastolic Dysfunction in Drosophila

Abstract

Due to its short lifespan, Drosophila melanogaster is a tractable system in which to study the effects of senescence on cardiac function. Female yellow‐white flies experience a significant decrease in diastolic diameter between 1 and 5 weeks of age (>20%). An atomic force microscopy‐based micromechanical analysis on the intact heart tubes of juvenile and geriatric flies revealed that their cardiomyocytes stiffen with age proximal to the intercalated discs (1.8 ± 0.13 to 3.8 ± 0.30 kPa). Another strain, white 1118, is significantly more arrhythmic but experiences less diastolic dysfunction with age (<10% decrease in diastolic diameter). White flies were found to have no change in stiffness with age (p > 0.10). These first in situ mechanical analyses of living myocardium have resolved differences in passive cardiac mechanics due to age and suggest that phenotype and mechanism differ significantly between Drosophila strains. DNA‐microarrays have identified a host of mechanically‐sensitive proteins to have significantly altered expression with age. Mechanical analysis of flies with RNA‐interference targeted against promising candidates indicates several molecular mechanisms of age‐related myocardial stiffening and diastolic dysfunction. [NIH 1T32HL105373‐01 to GK; NIH 1D092OD006460 to AJE; AHA 10SDG4180089 to AC]