New therapy strategies for desmin-related myopathies and cardiomyopathies

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Desmin is an intermediate filament protein, which is an essential component of the extra-sarcomeric cytoskeleton in striated muscle cells. The pivotal role of desmin is highlighted by the observation that mutations of the human desmin gene on chromosome 2q35 cause a clinically diverse group of autosomal-dominantly and -recessively inherited as well as sporadic myopathies and cardiomyopathies. To date neither specific nor ameliorating therapies are available for this group of progressive, severely disabling, and often premature lethal diseases. Based on our comprehensive work on the pathophysiology of desminopathies employing muscle tissue specimens from patients and from our desminopathy mouse models, we here plan to conduct an experimental, pre-clinical study addressing new therapeutic strategies. For this purpose, we will analyze the effects of acute and chronic physical exercise as well as of a pharmacological treatment with two repositioned drug candidates, i.e., the chemical chaperone 4-phenylbutyrate and the anti-oxidant N-acetylcysteine, in hetero- and homozygous R349P desmin knock-in and homozygous desmin knock-out mice. Specifically, we will address the following key questions: i) Is acute, strenuous treadmilling harmful to skeletal and cardiac muscle tissue in desminopathies? ii) To what extent is chronic, low-intensity treadmilling beneficial for striated muscle in desminopathies? iii) Does the application of 4-phenylbutyrate or N-acetylcysteine improve muscle strength or morphology in desminopathies? This project has the translational potential to improve the counselling of affected humans with regard to effects of physical activity. Moreover, our drug repositioning approach may provide the basis for a first pharmacological treatment in human desminopathy patients.