Obscurin deficiency leads to compensated dilated cardiomyopathy and increased arrhythmias

• DOI: 10.1085/jgp.202413696
• Publication Date: 2025-04-16T06:20:32Z
• Authors: Josè Manuel Pioner; Enrico Pierantozzi; Raffaele Coppini; Egidio Maria Rubino; Valentina Biasci; Giulia Vitale; Annunziatina Laurino; Lorenzo Santini; Marina Scardigli; Davide Randazzo; Camilla Olianti; Matteo Serano; Daniela Rossi; Chiara Tesi; Elisabetta Cerbai; Stephan Lange; Carlo Reggiani; Leonardo Sacconi; Corrado Poggesi; Cecilia Ferrantini; Vincenzo Sorrentino

Obscurin is a large muscle protein whose multiple functions include providing mechanical strength to the M-band and linking the sarcomere to the sarcoplasmic reticulum. Mutations in obscurin are linked to various forms of muscle diseases. This study compares cardiac function in a murine model of obscurin deletion (KO) with wild-type (WT) in vivo and ex vivo. Echocardiography showed that KO hearts had larger (+20%) end-diastolic and end-systolic volumes, reduced fractional shortening, and impaired ejection fraction, consistent with dilated cardiomyopathy. However, stroke volume and cardiac output were preserved due to increased end-diastolic volume. Morphological analyses revealed reduced sarcoplasmic reticulum volume, with preserved T-tubule network. While myofilament function was preserved in isolated myofibrils and skinned trabeculae, experiments in intact trabeculae revealed that Obscn KO hearts compared with WT displayed (1) reduced active tension at high frequencies and during resting-state contractions, (2) impaired positive inotropic and lusitropic response to β-adrenergic stimulation (isoproterenol 0.1 μM), and (3) faster mechanical restitution, suggesting reduced sarcoplasmic reticulum refractoriness. Intracellular [Ca2+]i measurements showed reduced peak systolic and increased diastolic levels in KO versus WT cardiomyocytes. Western blot experiments revealed lower SERCA and phospholamban (PLB) expression and reduced PLB phosphorylation in KO mice. While action potential parameters and conduction velocity were unchanged, β-adrenergic stimulation induced more frequent spontaneous Ca2+ waves and increased arrhythmia susceptibility in KO compared with WT. Taken together, these findings suggest that obscurin deletion, in adult mice, is linked to compensated dilated cardiomyopathy, altered E-C coupling, impaired response to inotropic agents, and increased propensity to arrhythmias.