propylthiouracil and Muscular-Dystrophy--Animal

1. Duchenne and Becker muscular dystrophies are X-linked disorders caused by defects in muscle dystrophin. The mdx mouse is an animal model for Duchenne muscular dystrophy which has a point mutation in the dystrophin gene, resulting in little (<3%) or no expression of dystrophin in muscle. Mdx mice show a characteristic pattern of muscle necrosis and regeneration. Muscles are normal until the third postnatal week when widespread necrosis commences. This is followed by muscle regeneration, with the persistence of centrally nucleated fibres. 2. This work has examined the hypothesis that the onset of this muscle necrosis is associated with postnatal maturation of the thyroid endocrine system and that pharmacological inhibition of thyroid hormone synthesis delays the onset of muscle necrosis. 3. Serum T4 and T3 concentrations of mice were found to rise immediately before the onset of muscle necrosis in the mdx mouse, and induction of hypothyroidism by treatment of animals with propylthiouracil was found to delay the onset of muscle necrosis. 4. The results provide the first demonstration of experimental delay of muscle necrosis by manipulation of the endocrine system in muscle lacking dystrophin, and provide a novel insight into the way in which a lack of dystrophin interacts with postnatal development to precipitate muscle necrosis in the mdx mouse.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Body Weight; Disease Models, Animal; Dystrophin; Hypothyroidism; Mice; Mice, Inbred mdx; Muscle, Skeletal; Muscular Dystrophy, Animal; Propylthiouracil; Thyroxine; Triiodothyronine

We showed previously that propylthiouracil (PTU), a thyroid inhibitor, could alleviate several major signs of hereditary muscular dystrophy in chickens. The goals of the present investigation were to: (1) determine whether a nearly athyroid condition (achieved within two days after hatching by surgical thyroidectomy plus PTU) during an 11-day period beneficially affects the dystrophic condition when followed by triiodothyronine (T3) replacement to 33 days of age; (2) determine the beneficial effects on the expression of avian dystrophy when the thyroidectomized-PTU-treated chickens received a wide range of moderate to low T3 replacement doses beginning by two days after thyroidectomy; and (3) examine the thyroid hormone receptor system in dystrophic muscle for a possible abnormality. Thyroid deprivation increased muscle function (righting ability) and reduced plasma creatine kinase activity in dystrophic chickens. The major thyroid-related abnormality in dystrophic pectoralis muscles was an increased maximum binding capacity of solubilized nuclear T3 receptors.

Topics: Animals; Body Weight; Chickens; Creatine Kinase; Dose-Response Relationship, Drug; Injections, Subcutaneous; Kinetics; Muscular Dystrophy, Animal; Pectoralis Muscles; Phenotype; Propylthiouracil; Receptors, Thyroid Hormone; Thyroid Gland; Thyroidectomy; Time Factors; 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

Topics: Animals; Chickens; DNA; Glucosephosphate Dehydrogenase; Hypertrophy; Muscular Dystrophy, Animal; Pectoralis Muscles; Phosphogluconate Dehydrogenase; Propylthiouracil; Thyroid Gland; Thyroxine; Triiodothyronine