Cellular Mechanisms of T-System Remodelling in Cardiac Myocytes

• Applicant: Privatdozent Dr. Thomas Seidel
• Subject Area: Anatomy and Physiology ; Cell Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 505991664

Chronic heart failure and other heart diseases lead to pathological remodelling of the heart muscle cells (cardiomyocytes). The transverse tubular system (t-system), a dense network of tubular membrane structures, is particularly affected. Positioning L-type calcium channels of the cell membrane directly opposite to calcium channels inside the cell (ryanodine receptors), the t-system ensures that rapid and efficient contraction occurs immediately after electrical excitation of the cardiomyocyte. Pathological remodelling or loss of the t system disturbs this process of electromechanical coupling, resulting in decreased contraction force and velocity. This hinders recovery and leads to progression of heart failure. Preventing or reversing t-system remodelling is therefore considered as a promising future approach in heart failure therapy. However, to achieve this, the cellular processes underlying t-system remodelling, and, importantly, the signalling pathways that control these processes must be better understood.The overall goal of this research project is to elucidate the cellular processes and signalling pathways involved in t-system remodelling in heart failure. Specifically, this project has three aims: 1) To identify cellular signalling pathways that induce t-system degradation in cardiomyocytes. The hypothesis will be tested that inflammatory and hypertrophic downstream signals of protein kinase C are crucially involved. 2) To investigate cellular processes responsible for t-system loss and remodelling in cardiomyocytes. The hypothesis will be tested that endocytosis and related processes are involved in t-system loss and that these processes are over-activated after stimulation of protein kinase C. 3) To verify the results of aims 1 and 2 in intact animal and human myocardium, using a novel in-vitro technique for long-term cultivation of cardiac tissue. The hypothesis will be tested that the identified cellular signalling pathways and processes contribute to t-system remodelling also in beating myocardial tissue slices and that functional impairment results from these structural changes, i.e. weaker and slower contraction of the tissue slices.It is expected that the results of the project will provide important new insights into the causes of t-system alterations in heart failure and thus represent a step towards new therapeutic approaches.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Tilmann Volk