ELECTRON MICROSCOPY OF MYOPATHIES

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This proposal seeks support for the continuation of an investigative program of human and experimentally induced muscle diseases. The diseases are approached through analysis of the light microscopic and ultrastructural reactions of the muscle fiber, neuromuscular junction, intramuscular nerves and blood vessels. Individual diseases are studied systematically by combined light microscopic histochemistry, immunocytochemistry, phase and electron microscopy, immunoelectron microscopy and freeze-fracture electron microscopy. Whenever possible, the observations are quantitated by morphometric methods and correlated with available physiologic and biochemical data. In four newly recognized congenital myasthenic syndromes the mechanisms that lead to failure of neuromuscular transmission will be further investigated: In the syndrome associated with high conductance and fast closure of the AChR ion channel, the hypothesis will be tested that the transmission defect is conditioned by an endplate myopathy and focal AChR deficiency. In the syndrome with decreased release of ACh quanta, additional evidence will be sought that the disorder stems from a paucity of synaptic vesicles and that this could be due to a deficiency of a synaptic vesicle membrane associated protein. In the syndrome with a putative abnormality of ACh-AChR interaction, a search will be made for any ultrastructural correlate that might result in a reduced amplitude of the miniature endplate current. In the syndrome of AChR deficiency and short channel open time, detailed analysis of endplate ultrastructure, and of the distribution of alpha-bungarotoxin binding sites, AChR subunits alpha, delta and epsilon, and of the AChR-associated 43 kD protein will be carried out. In the recently recognized eosinophilia-myalgia syndrome, a disabling inflammatory disease now attributed to sensitization to a contaminant of L-tryptophan preparations, immunocytochemical and ultrastructural studies will be done to define immune effector mechanisms and their targets. An experimental model of microvascular injury to skeletal muscle induced by sensitization to cultured human endothelial cells will be investigated. The immunoelectron microscopic localization of dystrophin in normal human skeletal muscle will be reinvestigated to clarify whether it is, or is not, associated with subcellular organelles other than the plasma membrane. In the newly discovered mitochondrial encephalomyopathy due to coenzyme Q10 deficiency, the hypothesis will be tested that the disorder is caused by a defect in the mitochondrial biosynthesis of coenzyme Q10.