Getting to the heart of sub-cellular structure Sub-cellular structures called dyads play a crucial role in the contraction and relaxation of the heart, yet much remains to be learned about their structure and function. Professor William Louch tells us about the CARDYADS project’s work in investigating the structure of dyads and the consequences of altering their organisation, research which could hold important therapeutic implications The cardiac muscle cells in the heart contract when calcium rises, a process triggered at dyads, tiny junctions between two membranes. Dyads are therefore very important in regulating the contraction of these cells, known as cardiac myocytes, and the heart, an area that forms the primary research focus of the CARDYADS project. “The project aims to understand how these dyad structures are put together in the first place, which we know very little about. What keeps them together? What keeps them working? How does this change during disease?” says Professor William Louch, the project’s Principal Investigator. These structures are known to break down during disease, which disrupts the control of calcium release and the contraction of both cardiac myocytes and the heart. Professor Louch and his colleagues are investigating the structure of dyads in development, adulthood, and cases of heart failure to build a deeper understanding of the effects of structural changes. “We have access to a biobank here, and we have samples from healthy patients and transplant patients. We also use animal models,” he outlines. The dyads themselves are extremely small. “It’s Controlling Cardiomyocyte Dyadic Structure (CARDYADS) The Norwegian Research Council The South-Eastern Norway Regional Health Authority (Helse Sør-Øst) The National Association for Public Health (Nasjonalforeningen for folkehelsen) Professor William E. Louch Kirkeveien 177 4th floor, Building 7 0407 Oslo T: +47 23 01 68 00 E: w.e.louch@medisin.uio.no W: www.iemr.no
formed of two membranes, and they’re about 12-15 nanometres apart from each other,” explains Professor Louch. A t-tubule extends from the surface of the T-tubules (coloured green) from a ventricular cardiomyocyte.
function. But in cases of heart failure, those proteins are spread out, they’re dispersed.” Researchers are also investigating whether there any early indicators of these changes in the dyads, work which could hold important therapeutic implications. Maintaining the structure of the dyads could be an effective way of maintaining a healthy heart. “We’re learning that there are molecular anchors that hold the two membranes of the dyad together. They anchor the t-tubules to the sarcoplasmic reticulum, so they hold the two membranes together,” explains Professor Louch. “These anchors are lost during heart failure, which we think is probably a major part of the reason why the dyads are disrupted. One possible therapy could be to give patients more of these anchors.”
The project aims to understand how these dyad structures are put together in the first place, which we know very little about.
What keeps them together? What keeps them working? How does this change during disease? cardiac myocyte into the interior, close to the membrane of the sarcoplasmic reticulum. Together, these two membranes form the dyad; Professor Louch says there are clear differences in dyad structure between the healthy and disease state. “The t-tubules are disorganised in disease, they move further away. Also, the proteins present on the sarcoplasmic reticulum are disrupted,” he says. “There’s a very important protein called the ryanodine receptor, which is a calcium release channel. These proteins are typically close together, as a group, which helps them
This is more of a long-term goal however, and at the moment researchers are still characterising how the dyads are put together during development, and how they break apart during disease. New techniques like super-resolution microscopy are being applied to investigate how dyads are arranged on the nanometre scale. “We’re looking at how they’re put together, we’re learning about what keeps them together, and we’re testing out a few of the novel, important genes, mostly at the cellular level so far,” says Professor Louch.
William E. Louch received his PhD in Pharmacology in 2001 from Dalhousie University in Halifax, Canada, and is currently Professor of Medicine at Oslo University Hospital / University of Oslo in Norway. His research examines structure and function of normal and diseased cardiac myocytes, with particular focus on calcium homeostasis.
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