基因敲除
兰尼定受体
心功能曲线
兰尼碱受体2
基因剔除小鼠
下调和上调
内科学
内分泌学
体内
生物
医学
受体
细胞生物学
心力衰竭
生物化学
基因
生物技术
作者
Maartje Westhoff,Silvia Villar,Taylor L. Voelker,Phung N. Thai,Heather C. Spooner,Alexandre Dantas Costa,Padmini Sirish,Nipavan Chiamvimonvat,Eamonn J. Dickson,Rose E. Dixon
标识
DOI:10.1038/s41467-024-47847-8
摘要
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 Ca V 1.2 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 Ca 2+ 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.
科研通智能强力驱动
Strongly Powered by AbleSci AI