THE ROLES OF CYTOSKELETAL PROTEINS IN SKELETAL MUSCLE FUNCTION AND DISEASE

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Congenital myopathies are inherited diseases of skeletal muscle that typically present at birth or in early chilhood and are characterised by poor muscle tone and muscle weakness. This group of disorders includes nemaline myopathy, central core disease, congenital fiber type disproportion, and myotubular myopathy. All of these disorders are characterised by disorganisation of the sarcomere, the major structure within skeletal muscle cells that is involved in contraction. In nemaline myopathy patients, mutations have been found in five genes that encode proteins of the filamentous systems of the sarcomere. Therefore, the genes for other thin filament, thick filament and Z-line proteins are excellent candidates for these disorders. Research from our lab has identified a novel region of the sarcomere and the genes encoding the proteins present in this region provide additional candidates for the congenital myopathies. We will further characterise the proteins in this novel structure to determine its function and the role that it plays in muscle disease pathologies. In order to study the relationship between disease pathology and muscle weakness in nemaline myopathy, we generated a mouse model by expressing a mutant protein, a-tropomyosin slow, found in human patients in mice. All features of the disease found in humans are present in the mice. A key feature of this disease in mice is the ability for muscle cells to grow in diameter or hypertrophy to offset the muscle weakness. We will use these mice to trial therapies including hypertropy-inducing agents, to prevent and reverse muscle weakness. In addition, we will generate an additional mouse model for this disease with a mutation in a gene encoding another filamentous protein. A comparison of the two models using microarray analysis will help us identify additional genes that are being affected in this disease and to generate a molecular expression profile that will aid in the diagnosis of this disease.