Role of Tenascin-C in dystrophic cardiomyopathy

Duchenne muscular dystrophy (DMD) is a severe inherited illness caused by mutations in the gene encoding for the intracellular protein dystrophin. Progressive skeletal muscle weakness and wasting leading to loss of ambulation, respiratory failure, and premature death are the hallmarks of the disease. Besides skeletal muscle degeneration, DMD is also associated with severe cardiac complications including cardiomyopathy development and cardiac arrhythmias. These significantly contribute to the morbidity and mortality. Since the specific mechanisms responsible for the cardiac disease phenotype are poorly understood, current therapy approaches are not targeted, and only induce very limited benefit. Thus, in DMD patients, cardiomyopathy development can neither be prevented, nor can its progression effectively be slowed, and current cardiac arrhythmia management is unsatisfactory. The future challenge will be to identify and validate new and better therapeutic targets. The successful exploration of such targets req uires a more detailed understanding of the pathophysiology in the human dystrophic heart. In the present project, we will study the as yet unknown role of the extracellular matrix protein Tenascin-C in dystrophic cardiomyopathy. This protein is upregulated in the heart under many pathological conditions and known to be an important regulator of fibrosis and inflammation . Tenascin-C is also used as biomarker predicting the severity of a cardiomyopathy and mortality in patients. Significantly enhanced Tenascin-C levels were found in the serum of DMD patients, and in serum and cardiac tissue from animal models for the human disease. Preliminary experiments suggest that Tenascin-C drives fibrosis in the dystrophic heart, and impairs ion channel function and intracellular calcium handling in dystrophic cardiomyocytes. This suggests that this protein is a major player in the pathophysiology characteristic for the dystrophic heart. Studying the role of Tenascin-C in this disease condition in the course of the present project may thus expose a new therapeutic target for evidence-based and hence effective treatment of the cardiomyopathy in DMD patients.