Subcellular Remodeling of the T-Tubule Membrane System: The Limits of Myocardial Recovery Revealed?

Abstract

Article, see p 1632 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.1,2 Resulting 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.2 In 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.4 This 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.4 An example of interorganellar communication in cardiomyocytes is the important interaction of sarcolemma with SR during excitation-contraction (EC) coupling.5,6 In 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 L-type Ca2+ channels in the transverse tubule allows small amounts of Ca2+ into the cytosol, a quantity insufficient by itself to activate a contractile response. Rather, this Ca2+ acts as a messenger to trigger the release of Ca2+ from the SR to reach a …