Elucidating the role of the membrane repair protein, dysferlin, in cardiac physiology

This PhD aims to determine the role of the membrane repair protein dysferlin in preserving intracellular calcium handling during the ageing process by maintaining cardiac structure and function. Dysferlin is known to repair damaged cell membranes in skeletal and heart muscle but data from our laboratory suggests that dysferlin plays a role in controlling the structure and function of the calcium handling machinery. Existing data supports the concept that dysferlin prevents pathological ryanodine receptor calcium leak and preserves calcium homeostasis where dysferlin's absence promotes cardiac arrhythmias. Dysferlin's protective role appears to be particularly important during physiological stress and we suggest that loss of this dysferlin-dependent protective effect contributes to premature ageing. We predict that the age associated decrease in dysferlin expression allows deficits to be accumulated more quickly during stress thereby increasing frailty. By mimicking physiological stress at the cellular and whole heart level we will use cutting edge technologies to establish the structural and functional mechanisms by which dysferlin protects cardiac function during both acute and chronic mechanical stress. Specifically we will: i) establish the contribution of cardiac dysferlin to increased frailty during ageing, ii) determine the potential drivers of increased frailty and, iii) establish if increased frailty predicts arrhythmia susceptibility.