Subcellular Remodeling of the T-Tubule Membrane System
Authors: J. Eduardo Rame, Sergio Lavandero
Journal: Circulation (2017)

Impaired contractile function is the hallmark of systolic heart failure (HF).However, the exact mechanisms are not fully understood, and the resulting morbidity and mortality remain high despite significant advances in pharmacological and device therapies. 1,2Resulting from plasticity of cardiac responses to injury, called pathological remodeling, the human heart changes in size, shape, and function.The culmination of complex, interdependent changes in molecular signatures, gene expression, metabolic adaptations, and cellular structures, the response of the failing heart to pathological insults of mechanical overload, neurohormonal excess, and ischemia has been studied extensively. 2In addition, cardiomyocyte ultrastructural remodeling of subcellular organelles including sarcoplasmic reticulum (SR), sarcolemma (plasma membrane), mitochondria, myofibrils, and extracellular matrix has also been described during the development of HF. 3 Communication between subcellular organelles is extensive in eukaryotic cells, involving plasma membrane, endoplasmic reticulum, mitochondria, nucleus, and other organellar structures through specialized membrane domains in close proximity to one another. 4This communication relies on different protein entities, depending on the organelles involved, and controls key cellular processes in a spatial and temporal fashion including cell death, metabolism, and gene expression. 4An example of interorganellar communication in cardiomyocytes is the important interaction of sarcolemma with SR during excitation-contraction (EC) coupling. 5,6In this case, the transverse tubular system (T system) is the specialized membrane penetrating into the cardiomyocyte interior as an extensive network of T tubules which allows a rapid and synchronized transmission of the membrane action potential.Activation of Ltype Ca 2+ channels in the transverse tubule allows small amounts of Ca 2+ into the cytosol, a quantity insufficient by itself to activate a contractile response.Rather, this Ca 2+ acts as a messenger to trigger the release of Ca 2+ from the SR to reach a critical [Ca 2+ ] threshold and initiate a contractile response. 5This structural and functional Ca 2+ microdomain (called couplon) comprises elements of the sarcolemma (≥1 voltage-gated L-type Ca 2+ channels in the T system) and a group of type 2 ryanodine receptors (RyR2) in the SR. 5 This junction spans ≈12 nm. 7Alterations of Ca 2+ transients are a common feature of cardiomyocytes from failing myocardium and are thought to contribute to the progression of HF. 8 Moreover, in cardiomyocytes isolated from ventricles recovering contractile function by means of left ventricular assist device (LVAD) support, these abnormalities in Ca 2+ cycling have been demonstrated to improve. 9yocardial reverse remodeling is a complex phenotype marked by dynamic changes at multiple levels impacting cardiomyocyte contractile force and ventricular size and function. 10When the therapy of maximal mechanical unloading is superimposed on a program of HF therapies proven to impact reverse remodeling, improvement in Subcellular Remodeling of the T-Tubule Membrane SystemThe Limits of Myocardial Recovery Revealed?