The objective of this proposal is to better understand the factors regulating muscle mass in human neuromuscular disease. The focus is on myotonic dystrophy, a multisystemic autosomal dominant disorder characterized by progressive atrophy of muscle and in which it has been shown that muscle protein synthesis is decreased. These investigations will test the hypothesis that muscle wasting results from decreased muscle protein synthesis which is in turn the result of impaired hormonal action in myotonic dystrophy. Studies will be extended to include Duchenne dystrophy, an x-linked recessive disorder. Recently the genetic defect and gene product have been defined in DD and there is evidence for decreased muscle protein synthesis as well as preliminary evidence for hormonally- induced improvement is strength. Whole body protein synthesis estimated as non-oxidative flux, will be studied by a primed- continuous infusion protocol with both L-(113C,15N)-leucine and L- (ring2H5) phenylalanine. Muscle protein synthesis will be determined by measuring the increment of 13Cleucine into mixed skeletal muscle protein obtained by needle biopsy. The values obtained by assessment of tissue incorporation of isotope will be compared with values obtained by study of skeletal muscle with the forearm technique. These forearm studies will examine amino acid net flux, rate of appearance, and rate of disappearances for phenylalanine and for leucine as well as rate of amino acid oxidation for 13C-leucine. The effects of growth hormone on whole body and muscle protein synthesis will be studied in patients with myotonic dystrophy and appropriate controls. The effect of feeding on hormonal action will also be studied. The effect of corticosteroids and other agents on muscle mass and muscle protein synthesis will be studied in Duchenne dystrophy. These studies of diseased subjects are designed to restrict the number of clinical variables by studying only male subjects who are non-obese, ambulatory, and free of complicating illness or medication use. All studies include neuromuscular disease controls as well as normal subjects. To exclude nonspecific effects of muscle wasting data will control for muscle atrophy by relating data to muscle mass (creatinine excretion), to loan body mass (40K counting), and to forearm muscle area (magnetic resonance imaging). These studies will better define the nature of muscle wasting in the muscular dystrophies and may lead to new therapeutic approaches for these disorders.
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