Restoration of β-adrenergic responsivity in the aging heart.

Abstract

Progressive cardiac hypo-responsivity to β-adrenergic receptor (βAR)-stimulation occurs with aging, diminishing capacity to manage acute stress, and rendering the heart more vulnerable to systemic stressors including hypertension and diabetes. Disruption of this crucial regulatory mechanism reduces inotropic reserve and lowers the threshold for heart failure. Yet the causal links between aging and β-AR hypo-responsivity are unclear. Here, using electrophysiology, advanced imaging approaches and biochemistry, we propose a mechanism that explains this age-dependent hypo-responsivity, and a restorative measure to rejuvenate the aging heart. Our results indicate that cardiac Ca2+ channels CaV1.2 and type 2 ryanodine receptors display altered nanoscale distribution, and impaired βAR-stimulated reorganization and recycling with aging that limits their functional augmentation. We find that age-associated overexpression of bridging integrator 1 (BIN1) contributes to dysregulated endosomal recycling and disrupted trafficking dynamics of these channels. BIN1 knockdown restored βAR-signaling responsivity and inotropic reserve to youthful levels. Paired echocardiograms of old mice before and after BIN1 knockdown revealed a restoration in cardiac contractility in vivo. In conclusion, we find that βAR hypo-responsivity in the aging heart occurs in part due to expressional upregulation of BIN1 that contributes to deficits in the endosomal recycling pathway, resulting in enlarged endosomes, altered trafficking dynamics of cardiac Ca2+ channels, and limiting the plasticity of excitation-contraction coupling. We propose targeted BIN1 knockdown as a novel therapeutic strategy to rejuvenate the aging myocardium.