Probing Human Heart Disease in Drosophila

We have created numerous models of congenital heart disease and cardiomyopathies using the Drosophila heart as a genetic model system. These include models for long-QT cardiac arrhythmias, for dilated and restrictive cardiac disorders, for haplo-insufficiencies and polygenic interactions of transcription factors, exhibiting pronounced aggravation with age, and involving genetic pathways that are conserved from fly to human. For example, insulin/TOR and SREBP signaling, known to modulate growth and (lipid) metabolism in many organisms, can act autonomously within the myocardium to fine-tune cardiac performance that deteriorates with age or due to a high fat diet. A new genetic pathway we discovered to be critical for establishing adult heart function involves the cardiogenic determinant tinman/Nkx2-5, the microRNA miR-1 and the Rho-GTPase Cdc42 acting similarly in the adult heart of flies as well as mice. This shows that the Drosophila heart serves as an efficient discovery tool for conserved (polygenic) modulators of heart disease. Recently, we also developed a Drosophila model for High Fat Diet-induced (HFD) obesity and heart dysfunction associated with excessive cardiac fat accumulation, involving nutrient-sensitive TOR signaling. In a screen for other modifiers of obesity-associated heart dysfunction, we found a role for the fly homolog of PPAR-γ Coactivator-1 genes, PGC-1/Spargel in protecting the heart from HFD-induced cardiomyopathy