Structure and function of the cytoskeleton in cardiac and skeletal muscle

Sammanfattning: We have examined the functional and structural roles of the cytoskeletal protein desmin in cardiac and skeletal muscles using a genetically modified mouse (Des-/-) with the desmin gene ablated. Desmin forms filaments at the Z-disks in the striated muscle sarcomere, have connections to the sarcolemma and most likely align sarcomeres and whole cells. We have shown a decreased contractile function of heart (study I) and skeletal muscle (study II) from Des-/- mice, indicating an important functional role of desmin transmitting the generated muscle force between cells or aligning sarcomeres. The Des-/- soleus skeletal muscle has an increased fatigue resistance (study II), which we interprete to be caused by a remodulation of the myosin isoform composition towards increased amount of the slow isoform. The filament lattice, examined with X-ray diffraction, is wider in Des-/- soleus muscles, which indicates that desmin has a structural role in anchoring the contractile filaments actin and myosin (study III). We have examined the role of a human desmin mutation (L345P) found in cardiomyopathy. The mutated desmin gene was expressed in a mouse model to study cardiac and skeletal muscle function (IV). We observed moderate signs of striated muscle myopathy. Knowledge about the intermediate filament functions is important for future treatment of desmin related myopathies. We have used the desmin deficient mouse model to examine how ATP receptor functions can be altered during cardiomyopathy. We report that a P2Y11-like receptor is involved in mediating the ATP induced inotropic responses of the mouse heart and that this receptor function might be down-regulated in desmin deficient cardiomyopathy (V). Modulation of this receptor function could be of possible therapeutic importance.