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

TL;DR

This study shows that a potassium channel in fruit flies connects sleep and heart function, with effects worsening as the flies age.

Contribution

The study identifies an age-sensitive neurocardiac axis mediated by Shaker channels in Drosophila.

Findings

Shaker mutations cause age-dependent cardiac dysfunction and sleep loss in Drosophila.

Circadian disruption worsens cardiac and sleep defects, while time-restricted feeding partially reverses them.

Neuronal Shaker knockdown alone impairs cardiac function, indicating a neurocardiac regulatory axis.

Abstract

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.