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bioRxiv · 10.1101/2022.08.23.504979

Restoration of β-adrenergic responsivity in the aging heart

del Villar, S. G.·Westhoff, M.·Voelker, T. L.·Dickson, E. J.·Dixon, R. E.
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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 rejuvenated cardiac function and substantially reversed 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 revealed reduced systolic function in old mice. BIN1 knockdown using an adeno-associated virus serotype 9 packaged shRNA-mBIN1 restored the nanoscale distribution and clustering plasticity of ryanodine receptors and recovered Ca2+ transient amplitudes and cardiac systolic function toward youthful levels. Enhanced systolic function correlated 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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/504979v2_ufig1.gif" ALT="Figure 1"> View larger version (83K): org.highwire.dtl.DTLVardef@74aa8eorg.highwire.dtl.DTLVardef@16978dforg.highwire.dtl.DTLVardef@17ea02dorg.highwire.dtl.DTLVardef@460f06_HPS_FORMAT_FIGEXP M_FIG C_FIG

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del Villar, S. G., Westhoff, M., Voelker, T. L., Dickson, E. J., Dixon, R. E.. 2022-08-25. Restoration of β-adrenergic responsivity in the aging heart. https://doi.org/10.1101/2022.08.23.504979

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