The Muscle Cytoskeleton of Mice and Men Structural remodelling in desmin myopathies

.................................................................................. 5 ABBREVIATIONS........................................................................... 6 ORIGINAL PAPERS........................................................................ 7 INTRODUCTION........................................................................... 8 The muscle fibre cytoskeleton......................................................... 8 Intermediate filaments.................................................................. 8 Desmin and other IF proteins in developing muscles............................... 9 Desmin in mature skeletal and heart muscle cells.................................... 10 IF associated proteins................................................................... 10 The function of desmin.................................................................. 11 Desmin in damaged and pathological muscles........................................ 11 The desmin gene and mutant phenotypes in mice................................... 12 AIMS OF THE STUDY..................................................................... 14 MATERIALS AND METHODS.......................................................... 15 Animal subjects.......................................................................... 15 Human subjects.......................................................................... 15 Preparation and culture of satellite cells.............................................. 15 Enzymehistochemistry.................................................................. 16 Immunocytochemistry.................................................................. 16 Immunoelectron microscopy........................................................... 16 Conventional transmission electron microscopy.................................... 17 RESULTS...................................................................................... 18 Morphological characterisation of cardiac lesions in desmin K/O mice.......... 18 A muscle dystrophy develops in skeletal muscles of desmin K/O mice......... 21 IF and IFAPs in skeletal muscles of WT and desmin K/O mice.................. 23 IF and IFAPs in normal human skeletal muscles.................................... 23 Altered cytoskeletal organisation in a desmin myopathy.......................... 23 DISCUSSION................................................................................. 25 Desmin knock-out mice................................................................. 25 Human desmin myopathy.............................................................. 25 Morphological alterations in desmin cardiomyopathies............................ 26 Skeletal muscle morphology in desmin myopathies................................. 28 IF and IFAPs in desmin myopathies.................................................. 29 The cytoskeleton of neuromuscular and myotendinous junctions................ 30 Uncertainties and issues to be further investigated................................. 30 CONCLUSIONS.............................................................................. 33 ACKNOWLEDGEMENTS................................................................. 35 REFERENCES................................................................................ 36 PAPER I-V....................................................................................