| Backgroud: As in other eukaryotic cells, the structural and functional integrity of cardiac muscle cells depends on an extensive cytoskeletal system which consists of microfilaments, microtubules and intermediate filaments (IFs). Desmin, a muscle-specific IF, is encoded by a single gene and is evolutionarily conserved. The desmin IF lattice surrounds the Z-discs, interconnects them to each other and links the entire contractile apparatus to the sarcolemmal cytoskeleton, cytoplasmic organelles and the nucleus. This allows the formation of a continuous cytoskeletal network that could be involved in several diverse functions, including maintenance of cellular integrity, force transmission and mechanochemical signaling. Upregulation of desmin in the heart occurs in a number of cardiac disorders such as cardiac hypertrophy and congestive heart failure, and desmin mutations are associated with desmin-relatd myopathy (DRM) and idiopathic dilated cardiomyopathy. Desmin-related cardiomyopathy (DRC) is a major part of DRM. DRM is a sporadic and familial neuromuscular conditions of considerable clinical heterogeneity uniformly marked by the pathologic accretion of desmin. It may affect all three types of muscle: skeletal, cardiac and smooth muscle. Alterations in heart appeared as conduction defects, arrhythmias and congestive heart failure. The resultant DRC is often the main cause of death in DRM. So far, mutations in the desmin gene and the B-crystallin (CryAB) gene have been associated with DRM. As a lens protein, CryAB also posseses molecular chaperone function. It facilitated many aspects of protein folding, translocation, interaction and turnover. The presence of ubiquitin conjugates and CryAB in the protein deposit associated with aberrant desmin aggregates in muscle cells in sporadic and hereditary DRMs seems to link the potential ubiquitin-proteasome system (UPS) malfunction to the pathogenesis. UPS is an ATP-dependent nonlysosomal proteolytic pathway in the cytpsol of eukaryotic cells, where it catalyzes the selective degradation of short lived regulatoryproteins and the rapid elimination of proteins with abnormal conformation. Nearly all the most common neurodegenerative diseases such as Alzheimer's disease, Parinson's disease, Huntington's disease and Creutzfeldt-Jakob disease are characterized by accumulation aggregated protein with elevatd ubiquitin conjugates. Recently mutations in the UPS have been linked to several neurodegenerative diseases and congenital heart diseases. However, the special causal relation between protein aggregation, UPS activity, and pathogenesis has remained elusive. Three types of intercellular junctions: fasciae adherens, desmosomes and gap junctions, have been identified in the intercalated disc. Fasciae adherens and desmosomes provide mechanical anchorage for myofibrils and extramyofibrillar cytoskeleton to the polar sarcolemma, and provide end-to-end linkage between adjacent cells. Gap junctions facilitate the communicton of electrical signals and small molecules between adjacent cells. In the fasciae adherens, the barb ends of actin of terminal sarcomeres are believed to link to N-cadherin through binding to -actinin or vinculin, which binds to -catenin, which binds to -catenin and -catenin. In adult myocardium, N-cadherin/catenin complex is primarily localized to adherens junctions in intercalated discs where it serves as an attachment site for myofibrils, in addition to its structural role in maintaining myocyte adhesion.In desmosomes, desmin filaments are believed to link to the cadherin-family protein desmoglein and desmocolins via desmoplakin and plakoglobin (aslo refered to as y-catenin) . Gap junction channels play a critical role in the propagation of action potentials. Each gap junction channel is composed of two hexameric hemichannels (connexons) formed of subunit proteins called connexins. Three different connexins (Cx40, Cx43, and Cx45) are expressed by cardiac myocytes. Since desmin filaments longitudinally insert into the desmosomes at the intercalat... |
PDF Full Text Request