ArticlebioRxiv : the preprint server for biology2025
A Micro-Engineered Heart Tissue Model of Desmin-related Cardiomyopathy Caused by Mutant αB Crystallin.
Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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15 authors.
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Abstract
Protein quality control (PQC) is essential for maintaining sarcomere integrity in cardiomyocytes. α Crystallin B chain (CRYAB) R120G mutation disrupts CRYAB's chaperone activity, leading to aggregation of CRYAB and its client proteins (including Desmin), leading to Desmin-related cardiomyopathy (DRM). Prior experimental systems for modeling DRM linked to CRYAB require massive overexpression of CRYAB mutant isoforms, raising questions about translational relevance. Here, we establish the first model of CRYAB-linked DRM that uses genome-edited hiPSC together with isogenic controls, allowing us to study the impact of mutant CRYAB expressed at near endogenous levels. Within micro-engineered heart tissues (μHT), CRYAB-R120G mutant hiPSC-derived cardiomyocytes recapitulated key DRM hallmarks, including Desmin and CRYAB aggregation, contractile dysfunction, and increased vulnerability to PQC pathway inhibition. CRYAB-R120G mutant μHT also exhibited dysfunctional calcium-contraction coupling, which exacerbated contractile deficits at higher pacing frequencies. JAK1 inhibition with Itacitinib partially restored contractile function at higher pacing frequencies, suggesting JAK1 inhibition as a viable therapeutic strategy. By preserving human-specific structural and functional features, our µHT platform enables mechanistic characterization of proteotoxic cardiomyopathies and offers a scalable system for targeted drug screening.
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