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Plectin, a cytoskeletal linker protein with a multitude of functions affecting various cellular processes, interlinks intermediate filaments (IFs) with each other and anchors them to sites of strategic importance for the organization and performance of cells. Mutations in the human plectin gene (PLEC) cause several rare diseases that are grouped under the term plectinopathies. The most common disorder is autosomal recessive disease epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), which is characterized by skin blistering and progressive muscle weakness. Besides EBS-MD, PLEC mutations lead to EBS with nail dystrophy, EBS-MD with a myasthenic syndrome, EBS with pyloric atresia, limb-girdle muscular dystrophy type R17, or EBS-Ogna. Skeletal muscle biopsies from EBS-MD patients and plectin-deficient mice revealed severe dystrophic features with variation in fiber size, degenerative myofibrillar changes, mitochondrial alterations and pathological desmin-positive protein aggregates. Thus, most plectinopathies can be annotated among the expanding group of myofibrillar myopathies (MFM). In skeletal muscle, the interplay between plectin and desmin IFs is essential for fiber integrity and cytoarchitecture. Accordingly, the loss of IF network function and the concomitant increased mechanical vulnerability of myofibers are supposed to be underlying mechanisms of MFMs. Thus, we aim at investigating molecular mechanisms that lead to muscle dysfunction in plectin-related MFM, with a focus on IF network alterations.

Compromised function of either plectin or desmin (or other MFM proteins) leads to impaired skeletal muscle integrity including the generation of desmin-positive protein aggregates, ultimately resulting in progressive muscular dystrophy. In addition, components of cellular protein quality control mechanisms, including the ubiquitine-proteasome system, chaperones, and autophagy have been reported to accumulate in MFM muscles. Accordingly, we assess the involvement of protein degradation machineries in myopathic mouse muscles (MCK-Cre/cKO, P1d-KO, Des-KO) and plectin-deficient myoblasts. Moreover, pectin-deficient myoblasts, which closely mimic the pathological features of plectinopathy patients, provide a unique ex vivo system to explore phenotype rescue approaches (including genetic/biochemical manipulations, screening for appropriate drugs). Thus, we assess the cell-protective effects of various drugs modulating cell stress response and/or protein degradation pathways. While myoblast cell lines enable a pre-selection of effective treatments, the corresponding mouse lines will be used for evaluating effects on skeletal muscle function.

Beyond skin and skeletal muscle involvement, mutations in the human plectin gene PLEC also cause a broad spectrum of cardiac disease manifestations. However, very little is currently known about the role of plectin and its individual isoforms in normal and diseased hearts. Therefore, we investigate the consequences of plectin-deficiency on cardiac function, morphology, and biochemistry in plectin-deficient cell and mouse 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 of this project are bound to yield a more integrated picture of how the cardiac muscle copes with stress under normal conditions and in disease. Beyond deeper insights into the pathophysiology of plectin-related cardiac diseases, this project shall answer the question if, and to what extent, physical activity and specific drugs can alter the cardiac muscle pathology in plectinopathy cell and animal models.