Mechanical load regulates transverse-tubule structure and function in left ventricular cardiomyocytes
Author(s)
Ibrahim, Michael
Type
Thesis
Abstract
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.
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.
Date Issued
2012-05
Date Awarded
2012-11
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Terracciano, Cesare
Yacoub, Magdi
Gorelik, Julia
Publisher Department
National Heart and Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)