BIN1 knockdown rescues systolic dysfunction in aging male mouse hearts

Maartje Westhoff, Silvia G. Villar, Taylor L. Voelker, Phung N. Thai, Heather C. Spooner, Alexandre D. Costa, Padmini Sirish, Nipavan Chiamvimonvat, Eamonn J. Dickson and Rose E. Dixon ()
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Maartje Westhoff: University of California Davis
Silvia G. Villar: University of California Davis
Taylor L. Voelker: University of California Davis
Phung N. Thai: Davis
Heather C. Spooner: University of California Davis
Alexandre D. Costa: University of California Davis
Padmini Sirish: Davis
Nipavan Chiamvimonvat: Davis
Eamonn J. Dickson: University of California Davis
Rose E. Dixon: University of California Davis

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47847-8

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