NEUROMUSCULAR AND CNS DISEASES AND THEIR EXPERIMENTAL MODELS

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The Section runs the Laboratory of Muscle Enzyme Histochemistry than processes up to 300 muscle and nerve biopsies per year for diagnostic and research studies. Examined muscles are from patients with: neuromuscular manifestations related to systemic, autoimmune, viral, metabolic, endocrine or infectious diseases; primary neuromuscular disorders, such as polymyositis, dermatomyositis, neurogenic muscular atrophies, muscular dystrophies, post-polio syndrome, polyneuropathies, mitochondrial encephalomyopathies; and patients with biochemical and genetic muscle diseases, such as central core disease or hypertrophic cardiomyopathy. The Laboratory is also involved in the following immunological, biochemical and virological studies that examine the susceptibility of the muscle and nerve to immune or viral mediated injuries: (a) Study the regeneration of human muscle in health and disease and the maturation of satellite cells by examining the expression of neural cell adhesion molecules and laminins; (b) study the susceptibility of muscle and nerve to infection with retroviruses and the ability of HIV and HTLV-l or HIV and HTLV-l-infected lymphoid cells to infect human myotubes in culture and induce expression of MHC- antigens; (c) study the expression of the poliovirus receptor in human muscle in vivo and in vitro, and the ability of the poliovirus to infect and replicate in human myotubes; (d) study the effect of cytokines and lymphokines on human myotubes and examine in vitro if potentially therapeutic agents such as IVIg can inhibit their toxic or immunopotentiating effect; (e) examine the role of ICAM-I in enhancing myocytotoxicity in vivo and in vitro by promoting the adhesion of cytotoxic T cells to myotubes; (f) study the toxicity of AZT to muscle mitochondria, mitochondrial oxidative phosphorylation and mitochondrial DNA by applying AZT to human muscle in culture; (g) study the effect of L-carnitine in reversing the mitochondrial abnormalities induced by AZT on human myotubes in vitro; and (h) using animal models. These models will be employed to study: (1) the pathogenesis of retrovirus-induced inflammatory myopathy by examining muscles from monkeys infected with the simian immunodeficiency virus; (2) the mechanism of AZT-induced mitochondrial myopathy by examining the structural, metabolic and functional alterations in the muscle mitochondria of healthy rats injected with AZT; (3) the effect of L-carnitine in reversing or improving the AZT-induced myopathy in the rats; and (4) the mechanism by which dideoxycytidine induces neurotoxicity in healthy rats.