The pathological consequences of desmin mutations: lessons from man and mice
The intermediate filament protein desmin is a central component of the three-dimensional extra-sarcomeric cytoskeleton in muscle cells, which interlinks neighboring myofibrils and connects the myofibrillar apparatus with the subsarcolemmal cytoskeleton, myonuclei, mitochondria, intercalated discs as well as myotendinous and neuromuscular junctions. The pivotal role of desmin for the structural and functional integrity of striated muscle tissue is highlighted by the observation that mutations of the human desmin gene on chromosome 2q35 cause autosomal-dominant, autosomal-recessive, and sporadic myopathies and cardiomyopathies with marked phenotypic variability. To date, no specific treatment is available for this severely disabling and often lethal disease. To understand the key pathological effects of mutant desmin on the structure and function of striated muscle tissue in early, pre-symptomatic disease stages. Morphological, biochemical, proteomic, genetic and biomechanical analyses of cells and striated muscle tissues expressing mutant desmin (R349P desmin knock-in mice; human muscle biopsies). Mutant desmin inflicts a complex, multilevel pathology with deleterious effects on the formation and maintenance of the extra-sarcomeric intermediate filament network, mitochondrial functions and biomechanical stress resistance. Our analyses demonstrate that mutant desmin already leads to a disruption of the extra-sarcomeric intermediate filament network and severe mitochondrial pathology in the early disease stages of desminopathies. FINANCIAL SUPPORT: Grant support by the German Research Foundation (DFG) within the framework of the multilocation research group FOR1228 (SCHR 562/13-1).