Previous studies have suggested an abnormality in Cl-metabolism in Duchenne muscular dystrophy (DMD) fibroblasts. In order to further characterize this abnormality, we have studied mCl-distribution and permeability in 11 DMD and 12 normal fibroblast lines. Under steady-state conditions Cl-efflux in fibroblasts is observed to be biphasic, revealing the presence of two major subcellular compartments. Each compartment contains approximately half of the cellular C1-. The faster of the two observed efflux components is significantly higher in DMD than in control fibroblasts (P < 0.001). To determine the results of a similar increase in Cl-permeability on skeletal muscle action potentials, we have simulated the effects of increased Cl-conductance on muscle by using a computer model. Effects on the simulated action potential include lower rates of membrane depolarization, lower overpotential, longer duration, and lower input resistance. These effects are similar to those actually observed in DMD muscle.Duchenne muscular dystrophy (DMD) is the most serious and rapidly progressive of the muscular dystrophies. Inherited as an X-linked recessive trait, the disease affects the skeletal muscle of boys in early childhood. Affected muscles show pseudohypertrophic changes secondary to the appearance of fat cells, macrophages, and fibroblasts between the necrotic muscle fibers (1). Ultrastructural changes in organelles within the fibers are suggestive of a compromised membrane. In the context of these pervasive cellular changes it has been difficult to identify the inherited biochemical abnormality. Recent investigations have, therefore, included studies of tissues such as erythrocytes, lymphocytes, and fibroblasts, which are not directly involved in the pathology of the disease (2-5).We have described three abnormalities in the lysosomes of DMD fibroblasts: (i) a 7-fold increase of cytoplasmic lamellar bodies (6, 7); (ii) decreased activity of dipeptidyl aminopeptidase I, a lysosomal proteolytic enzyme; and (iii) decreased structure-linked latency of this enzyme. Decreased structurelinked latency of lysosome-bound dipeptidyl aminopeptidase I is correlated with a decrease in the apparent K1/2 (the concentration having half-maximal effect) for Cl1 of this chloride-requiring enzyme. This difference in K1/2 is present only in intact lysosomes and disappears when the lysosomal membrane is disrupted (8). The requirement for an intact membrane and the correlation between latency and K112 for Cl-suggested that increased chloride permeability might be an important part of the etiology of DMD (9). In this study we
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