Molecular choreography and trafficking in the aging myocardium

University Of California At Davis, Davis CA

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Abstract

Project Summary Aging is an independent risk factor for cardiovascular disease and with an aging global population there is an urgent need to increase health-span alongside the already increased lifespan, allowing people to live independent and healthy lives well into their old age. Cardiac aging is inevitably accompanied by a progressive deterioration in cardiac function, including loss of responsivity to β-adrenergic receptor signaling and impaired myocardial relaxation resulting in diastolic dysfunction but the molecular mechanisms that drive these functional deficits are not understood. Recent progress has identified prominent signs of endosomal pathway dysfunction in ventricular myocytes from old hearts, including endosomal enlargement and impaired endocytosis and recycling of sarcolemmal L-type Ca2+ channels, impairing their ability to respond to acute stress. The endosomal pathway regulates and controls the expression of sarcolemmal proteins by orchestrating their endocytosis, sorting, and subsequent recycling or degradation. Defects in this pathway are linked to aberrant protein aggregation and neuronal pathology in a host of neurodegenerative diseases, but most famously Alzheimer's disease. Abnormal protein aggregation is also a feature of cardiac aging. These aggregates are thought to contribute to diastolic dysfunction by stiffening the ventricles. In this project we hypothesize that age-associated deterioration of the endosomal pathway is a driver of the age-associated decline in cardiac function. This hypothesis will be rigorously examined in three specific aims. The first will study the broad consequences of age- associated endosomal traffic jams on cardiomyocyte sarcolemmal proteostasis, impaired stress responses and diastolic dysfunction by examining membrane protein expression and recycling in young and old ventricular myocytes. The second will examine the influence of altered phosphoinositide metabolism on endosomal dysfunction in the aging heart by resolving PI species levels in various membrane compartments using specific biosensors and lipid mass spectrometry. The final aim will investigate the impact of aging on endosomal trafficking and localization of key proteins involved in the endosomal pathway, with the goal of restoring youthful endosomal function using stabilizing chaperones and/or AAV9 packaged shRNA approaches. By addressing these specific aims, we hope to shed light on the intricate interplay between aging, endosomal trafficking, protein aggregation, and cardiac dysfunction. The findings from this comprehensive investigation may identify novel targets for development of therapeutic strategies aimed at mitigating the adverse effects of aging on cardiovascular health and to extend healthspan in the elderly.