Why do heart muscles lose their ability to contract in cardiomyopathy?

Investigating a novel role for the LINC complex in cardiomyocyte mechanotransduction (Ms Shanelle de Silva)

Heart muscle cells have a criss-cross network of protein molecules, called the cytoskeleton, that keep them in the correct shape. For the heart to beat, muscle cells need to change the shape of their cytoskeleton. Dr Zhang has previously shown that if part of the cytoskeleton called the LINC complex is broken, heart muscle becomes enlarged, stiff and rigid, preventing the heart from pumping blood properly. This is a condition called cardiomyopathy. The LINC complex is made up of a range of molecules present in high levels in skeletal and heart muscle which mechanically attaches the cell’s nucleus to the cytoskeleton. Mutations in genes responsible for these components have been linked to dilated cardiomyopathy, but it is not known exactly how they lead to this condition. Dr Zhang proposes that when the LINC complex is broken, it changes the way cells sense the stiffness of their surroundings. In turn, this changes how they respond to calcium levels, which normally trigger heart cells to contract. To determine if this theory is correct, this project will study mice heart cells which have been genetically engineered to have mutations in the components of the LINC complex. They will look at how the cells in these engineered mice reorganise their cytoskeletons in response to mechanical stress and calcium. Working out why these specific changes of the cell cause people to develop cardiomyopathy could lead to new treatments that help them in the future.