The tiny Drosophila fruit fly may pave the way to new methods for studying and finding treatments for heart disease, the leading cause of death in industrialized countries, according to a collaborative study by the Burnham Institute for Medical Research, UC San Diego (UCSD) and the University of Michigan.
The study reports that mutations in a molecular channel found in heart muscle cell membranes caused arrhythmias similar to those that are found in humans, suggesting that understanding how this channel’s activity is controlled in the cell could lead to new heart disease treatments. Led by Burnham’s Professor Rolf Bodmer, Ph.D., and Staff Scientist Karen Ocorr, Ph.D., these new results, to be published in Proceedings of the National Academy of Sciences, will be made available by priority publication at the journal’s website during the week of February 26, 2007.
"This study shows that the Drosophila heart can be a model for the human heart," said Burnham researcher Bodmer. "Fly hearts have many ion channels that also are present in human hearts, making it suitable to extend mechanistic insight found in the fly hearts to human heart function."
The researchers focused on a membrane channel in the tiny Drosophila heart called KCNQ. This membrane channel, found in flies and humans, regulates the heart’s ability to return to a relaxed state after beating. This ability is crucial to healthy cardiac functions, and the inability to return to a relaxed state results in arrhythmias, which can lead to more serious heart disease and sudden death. In both flies and humans, cardiac arrhythmia and dysfunctions become more common with age.
The team found that mutations in the fly’s single KCNQ gene led to severe arrhythmias that would be immediately fatal to a human, but not in this insect that does not rely on the heart for oxygen supply. Hearts in young flies with the KCNQ mutation exhibited prolonged heart contractions and irregular beats seen usually in older flies (and older people). To enable their study of the fly heart, the researchers created new methods to dissect the hearts, and quantify heart contractility and other functions by using a movie camera to capture fly’s cardiac activity.
"We started with Nick Reeves and James Posakony at UCSD, who originally made the mutant KCNQ fly for a different purpose. We then studied these mutants with the new heart function assays that Ocorr was developing in my lab. Subsequently, we worked with Martin Fink and Wayne Giles at UCSD to develop a computer program that would allow the automated quantification of heart beat parameters and arrhythmias from the video images," Bodmer said. In addition, collaborations with H.S. Vincent Chen at Burnham and Soichiro Yasuda and Joseph Metzger of the University of Michigan enabled measuring the fly’s electrocardiogram (ECG) and heartbeat force and tension, respectively.
"We now have a lot of methods to precisely assess heart function in the fly, which augments its usefulness as a genetic model for studying cardiac function," said Ocorr, who conducted most of these studies.
The study points to KCNQ as a major factor in heart disease, but Bodmer warns that much more research is needed to use it alone as a drug target. "The fact that heart functions deteriorate in the mutant flies during aging suggests that there are other channels and genes that contribute to cardiac aging," he said. "We need to better understand the regulatory systems that control the level and activity of known cardiac channels and other unknown factors involved in coordinated heart muscle contraction."
In fact, the researchers are now looking at identifying other genes that regulate KCNQ channel function and heart physiology, and—thanks to the short lifespan of Drosophila —can look at the effects of aging, which is much harder to do in mammals with a relatively long lifespan.
"There’s an amazing conservation of genes between flies and humans," Bodmer said. "We can now look at how heart function ages in a realistic timeframe."
In addition to first author Ocorr, and contributions from collaborators Reeves, Fink, Chen, Yasuda, Posakony, Giles and Metzger, Bodmer’s colleagues included Robert Wessells and Takeshi Akasaka at Burnham.
"The collaborative spirit at Burnham", said Bodmer, "greatly facilitated interactions among the researchers that brought this multidisciplinary study to fruition".
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