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This study identifies stress granule coarsening as a critical mechanism linking cardiac stress to arrhythmia risk. Researchers found that while initial stress granule formation in heart cells appears protective, the subsequent merging of these granules disrupts calcium channel organization and electrical signaling at structurally important sites like z-lines and intercalated discs. Preventing granule coarsening with nocodazole preserved normal cellular architecture and electrical activity, suggesting this transition represents a therapeutic target for preventing arrhythmias during cardiac stress.
Why it matters
This work reveals a specific cellular event that could be targeted to prevent dangerous heart rhythm abnormalities that occur early in cardiac disease, before heart failure develops. The findings suggest that preventing stress granule coarsening, rather than blocking their formation entirely, could provide a therapeutic strategy to reduce arrhythmia risk while maintaining the protective benefits of the initial stress response.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Arrhythmia risk rises early in many forms of cardiac stress, often before contractile failure is evident. Stressed cardiomyocytes accumulate biomolecular condensates, known as stress granules (SGs), whose contribution to this electrical vulnerability has been unclear. We mapped where SGs reside and followed their life cycle under acute and chronic oxidative stress across complementary model systems and assessed electrophysiological consequences with pharmacological tools targeting granule assembly, microtubule integrity, and calcium channel function. Under both stress regimes, SGs localized preferentially to z-lines and intercalated discs, marking these mechanically critical sites as hubs of condensate assembly. Merging of granules, referred to as coarsening, rather than initial formation, emerged as a pathological connection. Early granules were broadly cytoprotective, whereas progressive coarsening was accompanied by disruption of alpha-actinin and L-type calcium channel (Cav1.2) nanodomains and by shortening of action potential (AP) duration. Coarsened granules disorganized Cav1.2 nanodomains through a microtubule-dependent mechanism, and arresting coarsening with nocodazole preserved nanodomain integrity and restored AP morphology. The transition from nascent to coarsened SGs therefore represents a targetable inflection point, and limiting coarsening may prevent proarrhythmic remodeling during cardiac oxidative stress.