Bidirectional links between sleep regulation and cardiac physiology revealed by Drosophila modeling of genes at insomnia and cardiovascular disease loci

Insomnia is a common sleep disorder associated with negative long-term health outcomes, including cardiovascular disease (CVD). We selected 16 genes from 13 insomnia- and CVD- associated genetic loci and disrupted Drosophila melanogaster orthologs in neuronal or cardiac tissue to characterize their roles in regulating sleep and cardiac physiology. Neuronal disruption of four orthologs (APOB, FUR, CYP17A1, and TCF4) resulted in short-sleeping flies, and three (MRAS, HDAC9, and TDRKH) resulted in long-sleeping flies. Short-sleeping fly lines impacted cardiac physiology consistent with links between short or poor-quality sleep and increased CVD in humans. Conversely, heart-specific disruption of five orthologs (RASD1, PHACTR1, CNNM2, MRAS, and TCF4) led to defects in cardiac physiology, with varied effects on sleep. Heart-specific knockdown lines that altered fractional shortening, a measure of cardiac contractility, also influenced long and short sleep states. These findings reveal bidirectional relationships between sleep states and cardiac performance, representing a potential feedback loop linking insomnia and CVD.