Desmin Filaments and Desmin-Related Myopathy

Desmin is the major intermediate filament protein in muscle tissue. In skeletal and cardiac muscle, desmin filaments distribute in the intermyofibrillar space to link adjacent myofibrils to each other at the z disc level, to the sarcolemma via costameres and sarcoglycan-dystroglycan complexes, and insert into to the nuclear envelope. The desmin filament network contributes to the positioning organelles such as mitochondria. In cardiac muscle, desmin is enriched in the intercalated disk by association with desmosomes. Hence, desmin plays an important role in the structural integrity and mechanical tension transmission across the myocyte and perhaps in the communication between cytoskeleton and extracellular matrix. Germ-line ablation of the desmin gene (DES) in mice does not affect muscle formation in embryos but causes postnatal cardiac and skeletal myopathies that deteriorate with age. A large number of mutations in DES or its partner proteins (e.g., CRYAB) cause desmin-related myopathy (DRM), a heterogeneous group of muscle disease featured by the presence of DES-positive aberrant protein aggregates in myocytes. Both disruption of the DES filament network as result of the mutation and gained toxicity of the mutant proteins may contribute to DRM pathogenesis but the precise pathogenesis remains poorly understood. Studies on DRM patients and DRM cell and animal models have also provided new insight into protein quality control in muscle tissue. Chemical chaperones, priming the proteasome, and enhancing autophagy have been shown to delay the progression of experimental DRM.