chymostatin and Muscular-Dystrophy--Animal

The effect of the cathepsin B inhibitor chymostatin was studied in mice with an X chromosome-linked muscular dystrophy. Treatment for 7 weeks at a daily dose of 1 microgram/g body weight had no apparent beneficial effect: serum creatine kinase levels, histopathology and the activity of muscle cathepsin B were not significantly altered by the treatment.

Topics: Animals; Chymotrypsin; Female; Male; Mice; Mice, Inbred C57BL; Muscular Dystrophy, Animal; Oligopeptides

We studied the effect of chymostatin on dystrophic mice (C57BL/6J-dy). The locomotor activity of normal mice increased markedly, attaining a plateau at 8 weeks of age, whereas in dystrophic mice, it increased until the age of 7 weeks, and thereafter decreased gradually. Serum levels of creatine phosphokinase were significantly higher in dystrophic mice compared with normal mice, and dystrophic mice had a reduced muscle protein content. When 3-week-old dystrophic mice received chymostatin (1 mg/kg, i.p.), the decrease in locomotor activity was retarded, serum enzyme levels decreased significantly, and muscle protein content increased significantly. In addition, the survival time of treated dystrophic mice was prolonged. The locomotor activity, serum enzyme levels, and muscle protein content of normal mice were not affected by chymostatin. Therefore, we posit that chymostatin retarded the progression of dystrophy in mice.

Topics: Animals; Female; Male; Mice; Mice, Inbred C57BL; Muscle Proteins; Muscular Dystrophy, Animal; Oligopeptides

To learn more about the enzymes involved in protein catabolism in skeletal and cardiac muscle and to identify selective inhibitors of this process, we studied the effects of proteinase inhibitors on protein turnover in isolated muscles and on proteolytic activities in muscle homogenates. Chymostatin (20mum) decreased protein breakdown by 20-40% in leg muscles from normal rodents and also in denervated and dystrophic muscles. These results are similar to our previous findings with leupeptin. The related inhibitors pepstatin, bestatin, and elastatinal did not decrease protein breakdown; antipain slowed this process in rat hind-limb muscles but not in diaphragm. Chymostatin did not decrease protein synthesis and thus probably retards proteolysis by a specific effect on cell proteinase(s). In homogenates of rat muscle, chymostatin, in common with leupeptin and antipain, inhibits the lysosomal proteinase cathepsin B, and the soluble Ca(2+)-activated proteinase. In addition, chymostatin, but not leupeptin, inhibits the chymotrypsin-like proteinase apparent in muscle homogenates. In muscles depleted of most of this activity by treatment with the mast-cell-degranulating agent 48/80, chymostatin still decreased protein breakdown. Therefore inhibition of this alkaline activity probably does not account for the decrease in protein breakdown. These results are consistent with a lysosomal site of action for chymostatin. Because of its lack of toxicity, chymostatin may be useful in maintaining tissues in vitro and perhaps in decreasing muscle atrophy in vivo.

Topics: Animals; Calcium; Dithiothreitol; Iodoacetates; Mice; Muscle Denervation; Muscle Proteins; Muscles; Muscular Dystrophy, Animal; Oligopeptides; p-Methoxy-N-methylphenethylamine; Protease Inhibitors; Rats