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SPEG Deficiency Disrupts Excitation-Contraction Coupling in Human Cardiomyocytes via Impaired JPH2 Phosphorylation

ABSTRACT: Dilated cardiomyopathy is a major cause of heart failure, with genetic mutations playing a significant role in its pathogenesis. To explore the molecular mechanisms underlying this condition, we established a striated muscle preferentially expressed protein kinase (SPEG)-deficient human embryonic stem cell-derived cardiomyocyte model to investigate the role of SPEG in cardiac dysfunction. Our findings revealed that SPEG knockout resulted in increased cardiomyocyte volume, disorganized sarcomeres, and upregulated heart failure markers, recapitulating key features of cardiomyopathy. Functional analysis, including calcium transient and contractility measurements, revealed disrupted excitation-contraction coupling in SPEG-deficient cardiomyocytes. Transcriptomic analysis revealed disrupted calcium signaling, while Western blot analysis confirmed reduced phosphorylation of junctophilin-2 (JPH2) as central mechanisms underlying these defects. Pharmacological activation of L-type calcium channels with Bay K8644 effectively restored calcium handling, excitation-contraction coupling delay, and contractile function, offering a promising therapeutic avenue for SPEG-associated cardiomyopathy. This study establishes SPEG as a critical regulator of cardiac function through its role in JPH2 phosphorylation and calcium homeostasis, while the human-relevant model developed here provides a valuable platform for further investigating SPEG-associated cardiomyopathy and exploring potential therapeutic interventions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE293104 | GEO | 2026/03/27

REPOSITORIES: GEO

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