Our objective is to gain a better understanding of the causes of muscle wasting, by determining rates of whole body and muscle protein synthesis and degradation in patients with neuromuscular disease and in normals. The focus will be on myotonic dystrophy, the most prevalent form of muscular dystrophy, and a disorder in which current evidence suggests that muscle wasting is the consequence of decreasing anabolism. The stable isotope L-(1-13C) leucine will be used for study of protein synthesis by a primed-continuous infusion protocol. Muscle protein synthesis rates will be determined by measuring isotope incorporation into muscle biopsy samples. Results from patients with myotonic dystrophy will be compared with studies in normals and in appropriate controls with other neuromuscular diseases. These procedures will permit the calculation of rates of whole body protein synthesis and degradation and validation of studies of muscle protein synthesis. Muscle wasting will be quantitated with muscle mass estimates based on creatinine excretion and total body potassium (40K method). An independent estimate of muscle catabolism will be made by quantitation of 3-methylhistidine excretion. The potential confounding effects of hyperinsulinemia will be obviated by performance of studies on fasted subjects and on subjects in whom insulin secretion is suppressed by continuous somatostatin infusion while insulin, growth hormone, and glucagon are infused. The flux of leucine across skeletal muscle will be studied by the forearm technique during 13C leucine infusion. Blood flow will be measured by both strain gauge plethysmography and dye-dilution techniques. The rate of release of 3-methylhistidine by forearm muscle will be determined in order to estimate the rate of muscle protein breakdown. The possibility that agents affecting rates of muscle protein synthesis may have therapeutic potential in myotonic dystrophy will be explored. Males with myotonic dystrophy are frequently androgen-deficient. Preliminary data indicate that administration of testosterone to males with myotonic dystrophy increases muscle mass as estimated by creatinine excretion and total body potassium. The effect of this hormone on whole body and muscle protein synthesis and on urinary 3-methylhistidine excretion, will be investigated.
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