BIN1 knockdown rescues systolic dysfunction in aging male mouse hearts.
Nat Commun
; 15(1): 3528, 2024 Apr 25.
Article
en En
| MEDLINE
| ID: mdl-38664444
ABSTRACT
Cardiac dysfunction is a hallmark of aging in humans and mice. Here we report that a two-week treatment to restore youthful Bridging Integrator 1 (BIN1) levels in the hearts of 24-month-old mice rejuvenates cardiac function and substantially reverses the aging phenotype. Our data indicate that age-associated overexpression of BIN1 occurs alongside dysregulated endosomal recycling and disrupted trafficking of cardiac CaV1.2 and type 2 ryanodine receptors. These deficiencies affect channel function at rest and their upregulation during acute stress. In vivo echocardiography reveals reduced systolic function in old mice. BIN1 knockdown using an adeno-associated virus serotype 9 packaged shRNA-mBIN1 restores the nanoscale distribution and clustering plasticity of ryanodine receptors and recovers Ca2+ transient amplitudes and cardiac systolic function toward youthful levels. Enhanced systolic function correlates with increased phosphorylation of the myofilament protein cardiac myosin binding protein-C. These results reveal BIN1 knockdown as a novel therapeutic strategy to rejuvenate the aging myocardium.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Envejecimiento
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Canal Liberador de Calcio Receptor de Rianodina
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Proteínas Supresoras de Tumor
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Proteínas Adaptadoras Transductoras de Señales
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Miocardio
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Proteínas del Tejido Nervioso
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Nat Commun
Asunto de la revista:
BIOLOGIA
/
CIENCIA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos