The administration of corticosteroids to humans is usually associated with muscle weakness and atrophy. Recent studies of Duchenne dystrophy showed a remarkable, rapid increase in muscle strength with prednisone treatment. Duchenne dystrophy is an X-linked disease in which the gene lesion at Xp21 results in absence of the cytoskeletal protein dystrophin. There is, however, substantial human and animal model data that indicate that dystrophin deficiency is necessary but not sufficient to cause weakness. The focus of this proposal is to define the mechanism of the paradoxical increase in muscle strength in Duchenne dystrophy. Preliminary observations suggest that prednisone increases muscle mass in Duchenne dystrophy. The prednisone effect does not appear to be due to its anti- inflammatory action. The proposed studies will test the hypotheses (1) that prednisone increases muscle mass in Duchenne dystrophy by decreasing pathologically-accelerated muscle protein catabolism; (2) that this decrease in catabolism is the result of up-regulation of a hormone(s) that slows muscle protein breakdown; and (3) that prednisone alters expression of either dystrophin or the homologous chromosome 6-encoded protein, utrophin. To determine if the prednisone action is disease-specific, the effect of prednisone on muscle metabolism will be studied in patients with Duchenne dystrophy and compared with its effect in another neuromuscular disease with accelerated catabolism, facioscapulohumeral dystrophy. Short- term studies of prednisone will also be conducted in normal subjects. Muscle protein synthesis will be determined by stable isotope incorporation (13C leucine) in muscle during a primed-continuous infusion; muscle protein breakdown by 3-methylhistidine excretion; and muscle mass by creatinine excretion, total body potassium, and dual-energy x-ray absorptiometry. Prednisone-induced hormonal changes will be evaluated by obtaining growth hormone, IGF-1, insulin, and glucagon levels. Muscle dystrophin and utrophin content and localization in Duchenne dystrophy biopsies will be determined by Western blotting and immunofluorescence microscopy. These studies will determine if the prednisone effect is a generalized phenomenon in muscle destructive disorders and may shed light on the factor(s) that mediate the effect. The results may also suggest strategies for better treatment of the muscular dystrophies.
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