Getting to the heart of the matter with titin
In collaboration with an international team, Tanoto Foundation Professor Stuart Cook and Dr Sebastian Schaefer from Duke-NUS and the National Heart Centre Singapore have undertaken a study that has uncovered how mutations in the protein titin cause the symptoms of dilated cardiomyopathy (DCM). The insight from their research opens up new possibilities for the development of future treatments for the disease.
DCM is a genetic disease of the heart muscle that results in an enlarged heart with thin walls. As a result, the heart cannot pump blood efficiently which may lead to heart failure or premature death in patients. Titin is a muscle protein that acts as a molecular spring and helps keep the heart muscle elastic.
Previous studies have shown that mutations in titin contribute to around 20 per cent of DCM cases. While titin mutations are common – occurring in one in 50 people – not all mutations result in the deadly symptoms of DCM. This raises the question of how to identify dangerous titin mutations from benign ones.
Harnessing the recent advancements in technologies such as stem cell reprogramming and gene-editing, the team used patients’ stem cells to generate heart muscle tissues in culture. This was then used to study the effects of mutated titin and its contribution to the pathology of DCM.
Results of the study, published in Science, suggest that the titin mutations are associated with impaired muscle organisation and a reduction in the length of the contractile unit in muscle. Overall, this causes the heart muscle to lose its elasticity and sag, resulting in thinner walls and larger heart chambers as observed in DCM patients.
“This method has allowed us to study the complexities involved in DCM directly, without relying on animal models,” explained Dr Cook, Director of the Cardiovascular and Metabolic Disorder Programme at Duke-NUS. “Building on our findings, patients diagnosed with the disease could potentially be treated with strategies that enhance the production of the muscles’ contractile units or stimulate other molecular functions, like signalling, that we had found to be impaired.”