Cytoskeletal regulation of cardiomyocyte homeostasis in health and disease

• Lucie CARRIER, University Medical Center Hamburg (Germany)

• Benjamin PROSSER, Perelman School of Medicine, University of Pennsylvania (USA)

Heart failure, the inability of the heart to pump enough blood through the body, is a consequence of a loss of heart muscle and/or a change in the properties of heart muscle cells. It is usually studied on the level of the motor proteins or their regulation by calcium. This Leducq Cytoskeleton Network (LCN) targets a component that has not received enough attention – the cytoskeleton, a structure that helps cells to maintain their shape and internal organization. It is composed of actin, microtubules and intermediate filaments and, under normal conditions, powers motor protein contraction, cargo delivery, and the disposal of waste proteins. Recent studies by the network members demonstrated that myocytes from failing human hearts have too many and abnormally modified microtubules and intermediate filaments, and revealed the enzymes involved in these modifications. This opens the unique possibility to target microtubule and intermediate filament modification to improve cardiac function. By using sophisticated ultrastructural imaging techniques and machine learning, the LCN will evaluate how the altered cytoskeleton affects cardiomyocyte contractile function as well as mRNA delivery, protein synthesis and waste disposal in heart failure. The LCN will also examine what initiates the proliferation and modification of the cytoskeleton, and whether these drivers can be targeted to prevent or reverse cardiac dysfunction and heart failure. Support by the Fondation Leducq would empower the LCN team to explore an innovative and vastly unexplored territory in the heart disease space.