Résumé :
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Communication n° 587 Type VII glycogenosis, or Tarui's disease, is a muscular disorder characterized by the appearance of muscular fatigue, hemolysis and myoglobinuria after exercise. It is associated with an abnormal accumulation of muscle glycogen, due to an increase in its synthesis and a blockade of its mobilization. The underlying defect is a deficiency in muscle 6-phosphofructo-1-kinase isoenzyme (PFK-1M). In order to obtain a murine model of Tarui's disease, heterozygous and homozygous PFK-1M knock-out mice were generated by standard gene-targeting methods in mouse ES cells. Heterozygous mice showed a 50% decrease in muscle PFK-1M mRNA levels, which led to a 50% decrease in muscle enzyme activity. This decrease did not cause alterations in muscle glycogen levels. Neither expression of the gene nor activity of the enzyme was found in skeletal muscle extracts from homozygous mice. These animals showed a three-fold increase in muscle glycogen levels and morphological abnormalities in muscle fibers such as necrotic and regenerating fibers or altered mitochondrias. Histopathological analysis of other tissues revealed glycogen accumulations in cardiac muscle and diaphragm. Moreover, due to the loss of erythrocyte PFK-1M activity, these animals showed higher levels of circulating reticulocytes. In addition, the spleen of PFK-1M deficient animals was 5 times bigger than those in control animals, due to hemolysis and compensatory extramedullary erythropoiesis. Furthermore, these animals were intolerant to exercise as described in human patients. The results indicate that mice lacking PFK-1M show pathological alterations similar to those observed in patients with type VII glycogenosis. Thus, these animals are the first murine model of type VII glycogenosis in which the disease can be studied and gene therapy approaches can be assayed and developed.
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