Plectin function in normal and diseased hearts

Plectin is a cytoskeletal linker protein with a multitude of cellular functions. Its pivotal role in mechanical stress-bearing tissues in humans is highlighted by the fact that mutations in the human plectin gene (PLEC) cause a variety of skin and skeletal muscle diseases. The group of human plectinopathies thus far comprises five autosomal-recessive disorders, namely epidermolysis bullosa simplex with musculardystrophy (EBS-MD), EBS-MD with myasthenic syndrome (EBS-MD-MyS), limb girdle muscular dystrophy type 2Q (LGMD2Q), EBS with pyloric atresia (EBS-PA), and skin-only EBS, as well as the autosomal-dominant variant EBS-Ogna. Plectinopathies belong to the group of rare diseases with an incidence of less than 5 affected individuals in 10,000. Beyond skin and skeletal muscle involvement, PLEC mutations also cause a broad spectrum of cardiac disease manifestations. However, very little is currently known about the role of plectin in normal and diseased hearts. Moreover, no curative treatment is available for all human plectinopathies. In this project, we aim to investigate the consequences of plectin-deficiency on cardiac function, morphology, and biochemistry in plectin-deficient cell and animal models. Moreover, we will assess the impact of physical activities on the cardiac pathology and will try to ameliorate the cardiac pathology by treatment with selected drugs, thereby candidates for EBS-MD patients. The combined genetic, biochemical, cellular, molecular, and physiological approaches proposed here are bound to yield a more integrated picture of how the cardiac muscle copes with stress under normal conditions and in disease. We strongly believe that our project will open a completely new chapter in our current understanding of the role of plectin in normal and diseased cardiac tissue. Beyond deeper insights into the pathophysiology of plectin-related cardiac diseases, the outlined project shall answer the question if, and to what extent, physical activity and the chosen drugs can alter the cardiac muscle pathology in plectinopathy cell and animal models. Thus, our work also has the translational potential to improve the clinical counseling of patients and may help to pave the way towards new treatment options for plectinopathies.