Age-related cardiac disease model of Drosophila

Abstract

We have begun to study the genetic basis of deterioration of cardiac function in the fruit fly Drosophila melanogaster as an age-related cardiac disease model. For this purpose we have developed heart function assays in Drosophila and found that the fly's cardiac performance, as that of the human heart, deteriorates with age: aging fruit flies exhibit a progressive increase in electrical pacing-induced heart failure as well as in arrhythmias. The insulin receptor and associated pathways have a dramatic and heart-autonomous influence on age-related cardiac performance in flies, suggestive of potentially similar mechanisms in regulating cardiac aging in vertebrates. Compromised KCNQ and K(ATP) ion channel functions also seem to contribute to the decline in heart performance in aging flies, suggesting that the corresponding vertebrate gene functions may similarly decline with age, in addition to their conserved role in protecting against arrhythmias and hypoxia/ischemia, respectively. The fly heart is thus emerging as a promising genetic model for studying the age-dependent decline in organ function.

Figure 1

Pacing-induced heart failure as a function of age following external electrical pacing from outbred wild type offspring (yw x Canton S). Experiments were performed at both 25°C and 29°C for a period of seven weeks. Test temperature alone has no effect on failure rate (Χ²= 0.05, p=0.82). Pacing-induced failure rate is age-dependent for both genders at both temperatures (Χ²>40, p<0.0001). More than 90 flies were used for each sample point. From Wessells et al. (2004).

Figure 2

(left hand panels) M-mode traces prepared from high speed movies of dissected flies with exposed hearts at one week (top) and five weeks of age (bottom). A 1 pixel-wide region with both edges of the heart tube is defined in a single movie frame. Same regions are electronically cut from all of the frames in the movie and aligned horizontally to produce the trace. (right hand panels) Histograms of the heart period lengths from the M-mode traces. Note the regular heart beat and corresponding narrow heart period distribution at one week; the incidence and severity of arrhythmicity increases with age (eg. at five weeks) and the heart period distribution broadens.

Figure 3

Cardiac dSUR function protects heart performance against electrical pacing. Heart failure rate after 30-second high frequency (6Hz) external pacing in one-week old RNAi-mediated knockdown mutants (progeny of UAS-dSUR-RNAi flies with the heart-specific GMH5 driver. Controls (progeny of GMH5 crossed with yw and yw crossed with UAS-dSUR-RNAi lines) show a low rate of heart failure. Conversely, cardiac dSUR knockdown results in significantly elevated levels of pacing-induced heart failure (*<0.01). Adapted from Akasaka et al. (2006).

Figure 4

dSUR K_ATP channel expression declines with senescence. (A) Relative expression of dSUR (0.15), tin (0.72), GFP (0.65) and SH3β (0.78) genes in five-week old hearts compared to hearts at one-week of age. Note the dramatic reduced dSUR RNA level with age compared to controls. (B,C) Electrical pacing-induced heart failure in flies treated with drugs that affect the mammalian sulfonylurea receptors. (B) One-week old yw flies fed with SUR blocker tolbutamide showed a higher heart failure rate than DMSO control-treated yw flies (45% and 25% respectively; p<0.01). (C) 3.5-week old yw flies fed with the K_ATP channel opener pinacidil showed a lower failure rate than DMSO-controls (26% and 42% respectively; p<0.02). From Akasaka et al. (2006).