Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1981 Apr;67(4):969–974. doi: 10.1172/JCI110147

In Vivo Effects of Protease Inhibitors on Chickens with Hereditary Muscular Dystrophy

Michael S Hudecki 1,2, Catherine M Pollina 1,2, Reid R Heffner 1,2
PMCID: PMC370654  PMID: 7204579

Abstract

Beginning on day 4 ex ovo, and every 3 d thereafter, genetically dystrophic Line 413 chickens were given intraperitoneal injections (4 mg/kg body wt) of a protease inhibitor, leupeptin, pepstatin, or antipain. Experimental chickens received protease inhibitors dissolved in a water:ethanol:dimethyl sulfoxide solution (50:40:10, vol:vol:vol). Control untreated animals received diluent injections.

Untreated dystrophic chickens typically reach around day 30 ex ovo a maximum ability to right from the supine position in a standardized functional test for muscle weakness. After day 30 ex ovo, the dystrophic chickens are found to decline progressively in their ability to right, compared with normal, nondystrophic controls, which have an unimpaired ability to right. Concomitantly, dystrophic chickens exhibit characteristically high levels of plasma creatine phosphokinase enzyme activity. In addition, an increased frequency of degenerating, regenerating, and vacuolated myofibers, and inflammatory cells appear in the affected pectoralis major muscles from the dystrophic chicken.

Throughout the duration of the trial, there was no major enhancement in the functional righting ability of dystrophic chickens receiving any one of the protease inhibitors tested. However, there was a significant reduction in the abnormally high levels of plasma creatine phosphokinase in the treated chickens. Also, there was an apparent reduction in the mean number of vacuolated fibers in the pectoralis muscle from the protease inhibitor-treated birds. No significant reductions were observed in the relative frequency of degenerating and regenerating myofibers or inflammatory cells. In addition to the plasma creatine phosphokinase decrease, however, therapeutic benefit was seen in 31.0, 30.5, and 14.8% increases in the wet weight (and total noncollagen protein) of pectoralis muscle from dystrophic chickens receiving leupeptin, pepstatin or antipain, respectively.

Full text

PDF
969

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Cabe P. A., Tilson H. A. Brief communication. Hind limb extensor response: a method for assessing motor dysfunction in rats. Pharmacol Biochem Behav. 1978 Jul;9(1):133–136. doi: 10.1016/0091-3057(78)90024-2. [DOI] [PubMed] [Google Scholar]
  2. Cabe P. A., Tilson H. A., Mitchell C. L., Dennis R. A simple recording grip strength device. Pharmacol Biochem Behav. 1978 Jan;8(1):101–102. doi: 10.1016/0091-3057(78)90131-4. [DOI] [PubMed] [Google Scholar]
  3. Chou T., Hill E. J., Bartle E., Woolley K., LeQuire V., Olson W., Roelofs R., Park J. H. Beneficial effects of penicillamine treatment on hereditary avian muscular dystrophy. J Clin Invest. 1975 Oct;56(4):842–849. doi: 10.1172/JCI108163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Enomoto A., Bradley W. G. Therapeutic trials in muscular dystrophy. III. Studies of microbial proteinase inhibitors in murine dystrophy. Arch Neurol. 1977 Dec;34(12):771–773. doi: 10.1001/archneur.1977.00500240059010. [DOI] [PubMed] [Google Scholar]
  5. Entrikin R. K., Patterson G. T., Weidoff P. M., Wilson B. W. Righting ability and skeletal muscle properties of phenytoin-treated dystrophic chickens. Exp Neurol. 1978 Sep 15;61(3):650–663. doi: 10.1016/0014-4886(78)90030-4. [DOI] [PubMed] [Google Scholar]
  6. Entrikin R. K., Swanson K. L., Weidoff P. M., Patterson G. T., Wilson B. W. Avian muscular dystrophy: functional and biochemical improvement with diphenylhydantoin. Science. 1977 Mar 4;195(4281):873–875. doi: 10.1126/science.841310. [DOI] [PubMed] [Google Scholar]
  7. Hudecki M. S., Barnard E. A. Retardation of symptoms of dystrophy in genetically dystrophic chickens by chemotherapy. Res Commun Chem Pathol Pharmacol. 1976 May;14(1):167–176. [PubMed] [Google Scholar]
  8. Hudecki M. S., Pollina C. M., Bhargava A. K., Hudecki R. S., Heffner R. R. Delayed functional disability in dystrophic chickens receiving chemotherapy. Muscle Nerve. 1979 Jan-Feb;2(1):57–67. doi: 10.1002/mus.880020109. [DOI] [PubMed] [Google Scholar]
  9. Hudecki M. S., Pollina C. M., Bhargava A. K., Hudecki R. S. Screening of antiserotoninergic drugs with the genetically dystrophic chicken. Arch Neurol. 1980 Sep;37(9):545–550. doi: 10.1001/archneur.1980.00500580041005. [DOI] [PubMed] [Google Scholar]
  10. Hudecki M. S., Pollina C., Bhargava A. K., Fitzpatrick J. E., Privitera C. A., Schmidt D. Effect of exercise on chickens with hereditary muscular dystrophy. Exp Neurol. 1978 Aug;61(1):65–73. doi: 10.1016/0014-4886(78)90181-4. [DOI] [PubMed] [Google Scholar]
  11. Iodice A. A., Chin J., Perker S., Weinstock I. M. Cathepsins A, B, C, D and autolysis during development of breast muscle of normal and dystrophic chickens. Arch Biochem Biophys. 1972 Sep;152(1):166–174. doi: 10.1016/0003-9861(72)90204-4. [DOI] [PubMed] [Google Scholar]
  12. Iodice A. A. The inhibition by pepstatin of cathepsin D and autolysis of dystrophic muscle. Life Sci. 1976 Nov 1;19(9):1351–1358. doi: 10.1016/0024-3205(76)90433-1. [DOI] [PubMed] [Google Scholar]
  13. Ionasescu V., Ionasescu R., White D., Feld R., Cancilla P., Kaeding L., Kraus L., Stern L. Altered protein synthesis and creatine kinase in breast muscle cell cultures from dystrophic chick embryos. J Neurol Sci. 1980 May;46(2):157–168. doi: 10.1016/0022-510x(80)90074-x. [DOI] [PubMed] [Google Scholar]
  14. Kar N. C., Pearson C. M. Muscular dystrophy and activation of proteinases. Muscle Nerve. 1978 Jul-Aug;1(4):308–313. doi: 10.1002/mus.880010407. [DOI] [PubMed] [Google Scholar]
  15. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  16. Libby P., Goldberg A. L. Leupeptin, a protease inhibitor, decreases protein degradation in normal and diseased muscles. Science. 1978 Feb 3;199(4328):534–536. doi: 10.1126/science.622552. [DOI] [PubMed] [Google Scholar]
  17. McGowan E. B., Shafiq S. A., Stracher A. Delayed degeneration of dystrophic and normal muscle cell cultures treated with pepstatin, leupeptin, and antipain. Exp Neurol. 1976 Mar;50(3):649–657. doi: 10.1016/0014-4886(76)90034-0. [DOI] [PubMed] [Google Scholar]
  18. Munsat T. L., Baloh R., Pearson C. M., Fowler W., Jr Serum enzyme alterations in neuromuscular disorders. JAMA. 1973 Dec 24;226(13):1536–1543. [PubMed] [Google Scholar]
  19. Munsat T. L., Bradley W. G. Serum creatine phosphokinase levels and prednisone treated muscle weakness. Neurology. 1977 Jan;27(1):96–97. doi: 10.1212/wnl.27.1.96. [DOI] [PubMed] [Google Scholar]
  20. Pennington R. J. Biochemistry of dystrophic muscle. 2. Some enzyme changes in dystrophic mouse muscle. Biochem J. 1963 Jul;88(1):64–68. doi: 10.1042/bj0880064. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Pennington R. J., Robinson J. E. Cathepsin activity in normal and dystrophic human muscle. Enzymol Biol Clin (Basel) 1968;9(3):175–182. doi: 10.1159/000458253. [DOI] [PubMed] [Google Scholar]
  22. Peterson D. W., Lilyblade A. L., Bond D. C. Proteolytic activity during growth of hypertrophic and atrophic muscles of genetically dystrophic chickens. Proc Soc Exp Biol Med. 1972 Dec;141(3):1056–1062. doi: 10.3181/00379727-141-36932. [DOI] [PubMed] [Google Scholar]
  23. Schorr E. E., Arnason B. G., Aström K. E., Darzynkiewicz Z. Treatment of mouse muscular dystrophy with the protease inhibitor pepstatin. J Neuropathol Exp Neurol. 1978 May;37(3):263–268. doi: 10.1097/00005072-197805000-00004. [DOI] [PubMed] [Google Scholar]
  24. Stracher A., McGowan E. B., Shafiq S. A. Muscular dystrophy: inhibition of degeneration in vivo with protease inhibitors. Science. 1978 Apr 7;200(4337):50–51. doi: 10.1126/science.635570. [DOI] [PubMed] [Google Scholar]
  25. Sugita H., Ishiura S., Suzuki K., Imahori K. Ca-activated neutral protease and its inhibitors: in vitro effect on intact myofibrils. Muscle Nerve. 1980 Jul-Aug;3(4):335–339. doi: 10.1002/mus.880030410. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES