Transverse tubule remodelling: a cellular pathology driven by both sides of the plasmalemma?
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Transverse (t)-tubules are invaginations of the plasma membrane that form a complex network of ducts, 200–400 nm in diameter depending on the animal species, that penetrates deep within the cardiac myocyte, where they facilitate a fast and synchronous contraction across the entire cell volume. There is now a large body of evidence in animal models and humans demonstrating that pathological distortion of the t-tubule structure has a causative role in the loss of myocyte contractility that underpins many forms of heart failure. Investigations into the molecular mechanisms of pathological t-tubule remodelling to date have focused on proteins residing in the intracellular aspect of t-tubule membrane that form linkages between the membrane and myocyte cytoskeleton. In this review, we shed light on the mechanisms of t-tubule remodelling which are not limited to the intracellular side. Our recent data have demonstrated that collagen is an integral part of the t-tubule network and that it increases within the tubules in heart failure, suggesting that a fibrotic mechanism could drive cardiac junctional remodelling. We examine the evidence that the linkages between the extracellular matrix, t-tubule membrane and cellular cytoskeleton should be considered as a whole when investigating the mechanisms of t-tubule pathology in the failing heart.
KeywordsTransverse tubules Excitation–contraction coupling Heart failure Extracellular matrix Collagen
We thank Auckland City Hospital and St. Vincent’s Hospital staff for assistance in obtaining tissue, and transplant recipients and donor families for donating tissue. Research funding was provided by the Auckland Medical Research Foundation (grant nos. 111009 and 1115014), Health Research Council of New Zealand (grant no. 12/240), Royal Society United Kingdom (grant no. RG.IMSB.107729) and Wellcome Trust (grant no. RG.IMSB.104532.054).
Compliance with ethical standards
Conflict of interest
David J. Crossman declares that he has no conflict of interest. Isuru D. Jayasinghe declares that he has no conflict of interest. Christian Soeller declares that he has no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.
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