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Title: Mechanical load regulates transverse-tubule structure and function in left ventricular cardiomyocytes
Author: Ibrahim, Michael
ISNI:       0000 0004 2732 438X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Chronic mechanical load variation triggers a wide range of responses in the heart, a part of which includes cellular remodelling. Over the past 15 years, evidence has amassed that a part of this remodelling process involves changes to a sophisticated structure in the cell membrane, called the transverse (t)-tubule system. The t-tubules are a series of regular membrane invaginations, which contain a high density of ion channels responsible for local Ca2+ induced Ca2+ release (CICR). This thesis addresses the question of whether the t-tubule system can be said to be specifically load sensitive, the nature of that load sensitivity and its molecular regulators. Using surgical models, the influence of mechanical load variation of different durations, degrees and settings are studied. Local CICR and t-tubule structure are investigated. First, it was found that prolonged mechanical unloading induces subtle changes to the t-tubule system, which functionally uncouples the Ryanodine receptors (RyR) and L-type Ca2+ channels (LTCC) and induces a loss of whole cell Ca2+ release synchrony. Second, heart failure was found to be associated with loss of t-tubule structure and Ca2+ handling abnormalities. Following mechanical unloading, the t-tubule system recovered with enhanced LTCC-RyR uncoupling, resulting in improved Ca2+ handling. Third, the t-tubules were found to be unchanged initially during graded mechanical load variation. Prolonged myocardial unloading or overloading impaired t-tubule structure, with loss of normal CICR. Telethonin (Tcap), a member of the cardiomyocyte stretch sensing complex, is a candidate regulator of the t-tubules. In a Tcap knock-out (KO), cardiomyocytes show a primary t-tubule defect, which becomes more pronounced following mechanical overload. These results support the notion that the t-tubule system is dynamically regulated by mechanical overload and unloading, via a molecular pathway including Tcap.
Supervisor: Terracciano, Cesare ; Yacoub, Magdi ; Gorelik, Julia Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral