Telomere dysfunction in cardiomyopathy in Duchenne and Becker Muscular Dystrophy
Mechanisms underlying how telomeres cause cardiac dysfunction
We have discovered an unexpected link between telomere shortening and genetic cardiomyopathies in human heart tissue- a highly unexpected finding given that telomere shortening normally required cell division and cardiomyocytes do not divide. Duchenne muscular dystrophy (DMD) is caused by the lack of dystrophin, a protein linking the cytoskeleton to the extracellular matrix. DMD patients die from dilated cardiomyopathy, which is characterized by extensive cardiomyocyte death and fibrosis that results in tissue stiffening and increased contractile resistance. Our mouse model for DMD and work by others support the role of long telomeres as cardioprotective. Our current goal is to identify a functional connection between contractile stress and telomere attrition that leads to cardiomyocyte death. We're specifically interested in how the rate of telomere attrition is impacted by increased contractile load, as well as how impaired mitochondrial function, reactive oxygen species, and DNA damage contribute to cardiomyocyte death.
Gene therapy approaches to treating DMD and BMD
Becker and Duchenne muscular dystrophy (BMD and DMD) are caused by a deficiency in dystrophin, a large cytoskeletal protein that links the actin cytoskeleton to the extracellular matrix. Efforts to reduce the size of dystrophin to essential domains have made it amenable to packaging into adeno-associated virus and effective in improving skeletal muscle function. Cardiac complications are common in BMD and DMD, however surprisingly little is known about the functional benefit of microdystrophin in cardiomyocytes. There are three clinical trials testing different microdystrophins, though none adequately address potential cardiac outcomes. We are comparing different versions of these microdystrophins in cardiomyocytes differentiated from induced pluripotent stem cells with deficiencies in dystrophin to distinguish the most effective gene therapy for the heart.
Dystropin domains included in microdystrophin designed for ongoing clinical trials.
Traction force microscopy of sarcomeres
Cardiomyocytes are the cells responsible for the contraction of the heart. Many heart disease are directly linked to contractile dysfunction in these cells following toxicity or gene mutation, such as in Duchenne Muscular Dystrophy cardiomyopathy. Quantifying the contractile function in single cardiomyocytes is therefore essential to our understanding of heart disease and to the development of therapeutic strategies. We develop novel methods and algorithms to track and assess the production of contractile force by single cells cultured on biomimetic hydrogel and to link the cellular contraction to the intracellular contraction of the sarcomeres, the protein structures responsible for contraction.
TFM of cardiomyocyte sarcomeres