methimazole and Muscular-Dystrophy--Animal

We showed previously that thyroid antagonists and glucocorticoids partially alleviated the impaired righting ability and abnormally high levels of plasma creatine kinase activity in genetically dystrophic chicks. The goals of the present study were: (1) to ascertain whether the beneficial effects of methimazole (MMI; thyroid antagonist) on muscle function and plasma creatine kinase (CK) activity in dystrophic chickens are correlated with significant reduction in plasma triiodothyronine (T3) and thyroxine (T4); (2) to assess whether the MMI-induced thyroid changes are accompanied by increased plasma corticosterone level and/or changes in muscle glucocorticoid receptors which might account partially for the beneficial effects of MMI; and (3) to determine if plasma T3 and T4 are reduced in dexamethasone (DEX) treated dystrophic chickens which might account at least partially for the beneficial effects of DEX (a potent glucocorticoid) on avian dystrophy. The data show that beneficial effects of MMI are associated with reduced plasma levels of thyroid hormones and increased circulating levels of corticosterone. In addition, DEX actually increases plasma T3 levels. These differential effects indicate that reduced plasma thyroid hormone levels do not represent a common mechanism of beneficial drug effects in avian muscular dystrophy. On the other hand, elevated plasma glucocorticoid levels accompany the beneficial effects of both severe hypothyroidism and DEX treatment. The data also show that MMI induces down-regulation of muscle cytosolic glucocorticoid receptors which are higher than normal in dystrophic muscles.

Topics: Animals; Body Weight; Chickens; Corticosterone; Creatine Kinase; Dexamethasone; Male; Methimazole; Muscles; Muscular Dystrophy, Animal; Receptors, Glucocorticoid; Thyroid Gland; Thyroxine; Triiodothyronine

Serum concentrations of triiodothyronine (T3) and thyroxine (T4) were determined by radioimmunoassay in normal and genetically related muscular dystrophic chicks at 2 through 42 days ex ovo. There were no significant differences in T4 concentrations, but T3 concentrations were reduced about 35% below normal values in dystrophic birds at 14 to 42 days. The situation was reversed, however, on day 2, with T3 concentrations about 50% greater in dystrophic than in normal serum. Administration of T3 beginning on day 2 ex ovo did not alter phenotypic expression of dystrophic signs. Administration of the thyroid "antagonists," methimazole and propylthiouracil, however, significantly increased righting ability and reduced serum creatine kinase activity in dystrophic chicks. None of the administered substances improved the histopathology of dystrophic pectoralis major muscles. The data indicate that serum T3 concentrations may provide an early "marker" for avian dystrophy, and suggest that lowered serum T3 concentrations in older chicks may represent a compensatory response to the elevated serum T3 in newly hatched dystrophic chicks.

Topics: Animals; Chickens; Male; Methimazole; Muscular Dystrophy, Animal; Poultry; Propylthiouracil; Thyroxine; Triiodothyronine

Mice with hereditary muscular dystrophy have reduced levels of serum T3. To determine possible causes of T3 deficits, we evaluated pituitary thyrotroph ultrastructure by electron microscopy, thyroid gland morphology by light microscopy, and T4 to T3 conversion by measuring iodothyronine 5'-deiodinase activity. Differences were not evident between dystrophic and normal littermates in either the structure of pituitary thyrotrophs or thyroid tissues. Dystrophic mice, however, had only 50% the normal hepatic 5'-deiodinase activity. Cerebral 5'-deiodinase, which does not appear to contribute significantly to serum T3, was similar in normal and dystrophic mice. Submandibular gland concentrations of nerve growth factor and epidermal growth factor are reduced in dystrophic mice but can be increased by T4 treatment. To distinguish whether growth factor deficits are due to reductions in serum T3 or to deficiencies in T4 5'-deiodinase activity and subsequent T3 utilization within the salivary gland, we measured submandibular deiodinase activity. Gland homogenates were active in the deiodinase assay, but no differences were detected between normal and dystrophic mice. In order to evaluate tissue responses to reductions in circulating T4, we treated mice with methimazole. Structural analyses revealed that thyrotrophs in dystrophic mice were less stimulated than thyrotrophs in similarly treated normal littermates. Likewise, thyroid follicular cells appeared less active, and thyroid weights increased only 40-50% as much as in normals. Liver 5'-deiodinase activity decreased in both normal and dystrophic mice. Cerebral 5'-deiodinase activity increased more than 4-fold in normal females but only 2-fold in dystrophic females; 2- to 3-fold increases occurred in both normal and dystrophic males. In summary, the structure of pituitary and thyroid glands in dystrophic mice is similar to that of tissues from normal littermates, but hepatic conversion of T4 to T3 is reduced. When challenged by methimazole-induced reductions in serum T4, pituitary and cerebral tissues in dystrophic mice respond abnormally.

Topics: Animals; Cerebral Cortex; Female; Iodide Peroxidase; Liver; Male; Methimazole; Mice; Muscular Dystrophy, Animal; Peroxidases; Pituitary Gland; Propylthiouracil; Sex Factors; Submandibular Gland; Thyroid Gland