: 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.

Obscurin deficiency leads to compensated dilated cardiomyopathy and increased arrhythmias / Pioner, JM ; Pierantozzi, Enrico; Coppini, Raffaele; Rubino, Egidio Maria; Biasci, Valentina; Vitale, Giulia; Laurino, Annunziatina; Santini, Lorenzo; Scardigli, Marina; Randazzo, Davide; Olianti, Camilla; Serano, Matteo; Rossi, Daniela; Tesi, Chiara; Cerbai, Elisabetta; Lange, Stephan; Reggiani, Carlo; Sacconi, Leonardo; Poggesi, Corrado; Ferrantini, Cecilia; Sorrentino, Vincenzo. - In: JOURNAL OF GENERAL PHYSIOLOGY. - ISSN 0022-1295. - ELETTRONICO. - 157:(2025), pp. 0-0. [10.1085/jgp.202413696]

Obscurin deficiency leads to compensated dilated cardiomyopathy and increased arrhythmias

Pioner, JM;Coppini, Raffaele;Biasci, Valentina;Laurino, Annunziatina;Santini, Lorenzo;Scardigli, Marina;Olianti, Camilla;Tesi, Chiara;Cerbai, Elisabetta;Sacconi, Leonardo;Poggesi, Corrado;Ferrantini, Cecilia
;
2025

Abstract

: 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.
2025
157
0
0
Pioner, JM ; Pierantozzi, Enrico; Coppini, Raffaele; Rubino, Egidio Maria; Biasci, Valentina; Vitale, Giulia; Laurino, Annunziatina; Santini, Lorenzo;...espandi
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1423435
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