Circadian disruption exacerbates alcohol-induced cardiac injury through impaired cellular quality control and increased cardiomyocyte death.

Abstract

Circadian rhythms orchestrate 24-h oscillations in physiology and gene expression in many tissues, including the heart. Disruptions to these rhythms have been linked to increased cardiovascular risk and impaired cellular homeostasis. However, the extent to which circadian disruption influences cardiac responses to environmental stressors such as alcohol, remains poorly understood. Herein, we performed RNA-sequencing and transcriptomic analysis on hearts from C57BL/6 J mice exposed to alcohol for ten weeks and collected at two distinct circadian time points (Zeitgeber Time (ZT)8 and ZT20). Principal component analysis and differential expression profiling revealed robust time-of-day-dependent transcriptional programs induced by alcohol, with significant enrichment of pathways governing mitochondrial quality control, autophagy/mitophagy, ferroptosis, and key signaling nodes (FOXO, MAPK, AMPK, mTOR, HIF, Hippo). To investigate the impact of circadian disruption, we compared alcohol-challenged hearts from circadian disrupted and control mice. Circadian disruption markedly altered transcriptional profiles and pathways associated with cardiomyopathy and insulin resistance, while further amplifying dysregulation of quality control and stress signaling networks. At the cellular level, alcohol exposure reduced autophagosome formation in isolated adult cardiomyocytes and this decrease was exacerbated by circadian disruption. Further, circadian disruption impaired mitochondrial quality control by reducing ATP production, altering mitophagy, and mitochondrial dynamics, resulting in mitochondrial dysfunction. These alterations were accompanied by increased reactive oxygen species (ROS) production and elevated apoptotic cell death compared with either condition alone. Altogether, these findings demonstrate that circadian disruption exacerbates alcohol-induced molecular and cellular cardiac injury by compromising cellular quality control processes, mitochondrial integrity, and cell survival pathways. These findings identify mechanisms that may contribute to increased susceptibility to alcohol-induced cardiac dysfunction and may offer novel approaches to mitigate alcohol-related cardiac injury in shift-workers or individuals with disrupted circadian rhythms.