Dipeptidyl peptidases in human muscle disease

Kar, Nirmal C.; Pearson, Carl M.

doi:10.1016/0009-8981(78)90042-6

Cited by 32 publications

(11 citation statements)

References 15 publications

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“…Indeed, one report (13) has shown, contrary to our results on DMD fibroblasts, that DAP-I activity is increased in DMD muscle. The reason for this apparent discrepancy is not clear but it would support the belief that lysosomal "activation" in DMD muscle biopsies is a nonspecific tissue response to injury as opposed to the primary mechanism of cellular degeneration (1).…”

Section: Discussioncontrasting

confidence: 99%

“…Previous investigations on muscle tissue from DMD patients (11)(12)(13)(14)(15)(16)(17) have reported increases in lysosomal protease activity, whereas the results reported here show that total acid autoproteolysis as well as a number of specific lysosomal enzymes are unchanged in DMD fibroblasts. Indeed, one report (13) has shown, contrary to our results on DMD fibroblasts, that DAP-I activity is increased in DMD muscle.…”

Section: Discussioncontrasting

confidence: 89%

“…It is also well known that muscle tissue in DMD patients is undergoing extensive invasion by fibroblasts, macrophages, and fat cells (it is this invasion that gives rise to the pseudohypertrophy characteristic of this disease). The specific activity of DAP-I in human muscle is 36 nM/mg protein per h (13), whereas in cultured fibroblasts it averages 1,988 and 487 nM/mg protein per h for normal and DMD cells, respectively (our data). Consequently, invasion of DMD muscle by other cells in which only 2-8% of the total cellular protein were replaced by fibroblasts would be sufficient to cause an apparent 100% increase in DAP-I activity.…”

Section: Discussionmentioning

confidence: 49%

“…Consequently, invasion of DMD muscle by other cells in which only 2-8% of the total cellular protein were replaced by fibroblasts would be sufficient to cause an apparent 100% increase in DAP-I activity. This could therefore account for the observed activation of DAP-I in DMD muscle (13).…”

Section: Discussionmentioning

confidence: 82%

“…A major obstacle in biochemical studies of dystrophic muscle has been the extensive secondary changes that occur in the degenerating skeletal muscle which serve to obscure the primary error of metabolism. Thus, there are reports of alterations in the levels of DMD skeletal muscle lipids (2,3), adenylate cyclase activity (4)(5)(6), activity of the sarcotubular system (7), protein synthesis (8), plasma membrane structure (9,10) and the activity of several lysosomal proteases (11)(12)(13)(14)(15)(16)(17). The fact that nonmuscle tissues are also affected clinically, although less critically, has suggested that the primary error might also be expressed in other organ systems (1).…”

Section: Introductionmentioning

confidence: 99%

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Decreased Lysosomal Dipeptidyl Aminopeptidase I Activity in Cultured Human Skin Fibroblasts in Duchenne's Muscular Dystrophy

Gelman¹,

Papa²,

Davis³

et al. 1980

J. Clin. Invest.

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A B S T R A C T Several lysosomal enzymes were assayed in cultured human skin fibroblasts from patients with Duchenne's muscular dystrophy (DMD) and age-and sex-matched control patients (N). The activity of four glycosidases, cathepsin B, and total autoproteolysis at pH 4.0 were unchanged between the groups, but dipeptidyl aminopeptidase I (DAP-I, or cathepsin C) in the DMD cells was found to be only 30% as active as in the control cells (P < 0.003). This difference is not the result of a redistribution or loss of enzyme during homogenization because the difference occurs in all homogenate fractions. DAP-I activity existing in N and DMD fibroblasts behaves identically with respect to activation by chloride ion, activation by the sulfhydryl reducing agent dithiothreitol, changes in hydrogen ion concentration (pH), changes in substrate concentration (i.e., apparent Km values), and changes in temperature (i.e., apparent activation energies). Mixtures of N and DMD cell sonicates display an additivity in DAP-I activity. These results support the conclusion that the catalytic function of the DAP-I molecule is equivalent between N and DMD fibroblasts, and that the decrease in tissuespecific DAP-I activity probably results from the fact that fewer enzyme molecules are present in the DMD cells. These results are also an indication that these nonmuscle cells are expressing some of the phenotypic aspects of the genetic defect in DMD. Cultured human skin fibroblasts may therefore be a useful cellular model in DMD research.

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Section: Discussioncontrasting

confidence: 99%