Shaker potassium channel mediates an age-sensitive neurocardiac axis regulating sleep and cardiac function in Drosophila

The Shaker (Sh) gene in Drosophila melanogaster encodes a voltage-gated potassium channel essential for regulating neuronal excitability and cardiac function. While Sh's role in neuronal physiology, particularly in sleep regulation, is relatively well-studied, its contribution to cardiac physiology and inter-tissue communication remains poorly understood. This study explores the impact of Sh mutations (Shmns and Sh5) on heart function and sleep/circadian behaviors, aiming to uncover potential neurocardiac interactions in an age-dependent manner. Cardiac performance and locomotor/sleep activity were assessed in mutant and control flies across aging cohorts under both normal and circadian-disrupted conditions, with and without time-restricted feeding (TRF). Shmns mutants displayed progressive, age-dependent cardiac dysfunction, including increased heart period, elevated arrhythmicity index, prolonged systolic and diastolic intervals, and diminished heart rate and fractional shortening, as well as disorganization of actin-containing myofibrils. These defects were paralleled by severe sleep loss and hyperactivity, suggesting a strong link between sleep/circadian dysregulation and cardiac impairment. Circadian disruption further exacerbated both cardiac and behavioral phenotypes, whereas TRF partially ameliorated these defects, highlighting a modulatory role for feeding timing. Tissue-specific knockdowns of Sh in cardiac and neuronal tissues recapitulated both heart and sleep abnormalities, with neuronal knockdown alone significantly impairing cardiac function, supporting a neurocardiac regulatory axis. Altogether, our findings reveal that Shaker channels mediate a critical, age-sensitive interplay between sleep/circadian systems and cardiac homeostasis in Drosophila. This work provides mechanistic insight into neurocardiac communication and suggests that KCNA1-linked human channelopathies may similarly impact sleep and cardiovascular health, offering a potential translational framework for age-related disorders.