Stress Granule Coarsening Is a Pathological Inflection Point for Cardiac Electrophysiological Dysfunction.

Area of Science:

• Cardiovascular Biology
• Cellular Stress Response
• Cardiac Electrophysiology

Background:

• Cardiac stress increases arrhythmia risk, often preceding contractile dysfunction.
• Stressed cardiomyocytes form stress granules (SGs), but their role in electrical vulnerability is unclear.

Purpose of the Study:

• To investigate the role of stress granules (SGs) in cardiac electrical vulnerability under oxidative stress.
• To determine the impact of SG life cycle, particularly coarsening, on cardiomyocyte electrophysiology.

Main Methods:

• Mapping SG localization and life cycle in cardiomyocytes under acute and chronic oxidative stress.
• Utilizing pharmacological agents to target SG assembly, microtubule integrity, and calcium channels.
• Assessing electrophysiological consequences, including action potential duration and nanodomain integrity.

Main Results:

• Stress granules preferentially localized to z-lines and intercalated discs.
• Granule coarsening, not initial formation, correlated with pathological changes.
• Coarsened SGs disrupted alpha-actinin and L-type calcium channel (Cav1.2) nanodomains via a microtubule-dependent mechanism, shortening action potential duration.
• Arresting coarsening preserved nanodomain integrity and restored action potential morphology.

Conclusions:

• The transition from nascent to coarsened SGs is a critical, targetable event in cardiac stress.
• Limiting SG coarsening may serve as a therapeutic strategy to prevent proarrhythmic remodeling.
• Understanding SG dynamics offers insights into early electrical dysfunction during cardiac stress.