Restoration of β-adrenergic responsivity in the aging heart

Background Progressive cardiac hypo-responsivity to β -adrenergic receptor ( β AR)-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. Methods 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. Results Our results indicate that cardiac Ca2+ channels CaV1.2 and type 2 ryanodine receptors display altered nanoscale distribution, and impaired β AR-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 β AR-signaling responsivity and inotropic reserve to youthful levels. Conclusions In conclusion, we find that β AR hypo-responsivity in the aging heart occurs in part due to expressional upregulation of BIN1 that contributes to deficits in the endosomal 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. ![Figure][1] ### Competing Interest Statement The authors have declared no competing interest. [1]: pending:yes