Activated/uninhibited
calcineurin is both necessary and sufficient to induce
cardiac hypertrophy, a condition that often leads to
dilated cardiomyopathy,
heart failure, and
sudden cardiac death. We expressed constitutively active
calcineurin in the adult heart of Drosophila melanogaster and identified enlarged cardiac chamber dimensions and reduced cardiac contractility. In addition, expressing constitutively active
calcineurin in the fly heart using the Gal4/UAS system induced an increase in heart wall thickness. We performed a targeted genetic screen for modifiers of
calcineurin-induced cardiac enlargement based on previous
calcineurin studies in the fly and identified
galactokinase as a novel modifier of
calcineurin-induced
cardiomyopathy. Genomic deficiencies spanning the
galactokinase locus,
transposable elements that disrupt
galactokinase, and cardiac-specific RNAi knockdown of
galactokinase suppressed constitutively active
calcineurin-induced
cardiomyopathy. In addition, in flies expressing constitutively active
calcineurin using the Gal4/UAS system, a
transposable element in
galactokinase suppressed the increase in heart wall thickness. Finally, genetic disruption of
galactokinase suppressed
calcineurin-induced wing vein abnormalities. Collectively, we generated a model for discovering novel modifiers of
calcineurin-induced cardiac enlargement in the fly and identified
galactokinase as a previously unknown regulator of
calcineurin-induced
cardiomyopathy in adult Drosophila.