Periodic Reporting for period 2 - ProtMechanics-Live (Uncovering Protein Mechanics in Physiology and Disease)
Reporting period: 2022-12-01 to 2024-05-31
Striated muscles are the tissues that move us every day, whether they are our limbs or make our heart beat. When we think of them we generally idealize them as force generators that allow us to move an arm or pump blood from our heart. However, their function is much more complex, as they work as a support for more complex structures. This is the case of the myocardium, the cardiac muscle, which does not only generate contraction forces, but also maintains its shape and anatomy. This is as important as the cardiac contraction itself, since it enables the organ to withstand the tension exerted by blood pressure. The main actors in the structural function of the myocardium are on the one hand the muscle cells (known as cardiomyocytes) and the set of proteins that hold them together from a complex external network called the extracellular matrix (ECM). Inside cardiomyocytes, the shape and structure of the cell is largely maintained by a group of specialized proteins that establish the so-called cytoskeleton, in particular the sarcomeres, which are the microscopic minimal contractile units. Of all the proteins that form the sarcomere, titin stands out due to its size, as it is the largest encoded protein in vertebrates, and also due to its structural function, as it functions as a scaffold that preserves the structure of the sarcomere in each myocardial contraction-relaxation cycle. Mutations in titin are cause heart disease and myopathies. Despite the structural and medical importance of titin and other similar mechanical properties, many aspects of their function remain unknown, mostly due to the lack of tools to study the mechanical function of proteins in living cells. The goal of ProtMechanics-Live is to develop new tools to interfere with the mechanical properties of titin in living cardiomyocytes, with the aim of better understanding the biological function of titin and its connections with heart and muscle disease.
So far, we have validated several tools to modulate mechanical properties of titin in living cardiomyocytes. These toolsare uncovering novel molecular mechanisms sustaining a healthy heart, which are currently being studied in detail.
The new tools we are developing are first-of-their-kind, so we are contributing to move the field of protein mechanics beyond the current state of the art. The expected results include molecular characterization of how complex biological systems react to changes in the mechanical properties of proteins.