POSSIBLE ROLE OF FIBRONECTIN IN THE PATHOGENESIS OF DUCHENNE'S MUSCULAR DYSTROPHY.

Abstract

Fibronectin (FN) is a critical component of the extracellular matrix (ECM) of fibroblasts and muscle cells and contributes to the maintenance of cell cytoskeleton, shape, migration, growth and differentiation. Extensive accumulation of both collagen and FN occurs in skeletal muscle of patients with Duchenne's muscular dystrophy (DMD). Several researchers have recently claimed that FN can interfere with proper muscle differentiation. Our hypothesis is that DMD fibroblasts or muscle cells fail to regulate properly the type, synthesis, or secretion of FN and that the increased accumulation FN in the ECM of fibroblasts in muscle may interfere with myogenesis, thus presenting the typical picture of regenerating but largely non-functional muscle in DMD. This was tested by labeling cultures of fibroblasts from DMD patients and controls with ³⁵S-methionine and quantitating basal levels of FN synthesis and degradation by immunoprecipitation. Collagen, FN and other components were measured in DMD sera and the metabolic effects of culturing DMD and control fibroblasts in the presence of DMD sera were studied. Muscle biopsies from DMD patients were examined for factors which might contribute to the accumulation of connective tissue. Increased levels of FN were measured in sera and cultured fibroblasts from DMD patients. Concomitant increases in other ECM components (collagen, glycosaminoglycans) were measured. The FN accumulation is at the expense of other cellular proteins as RNA and protein synthesis are reduced in DMD fibroblasts. Protein degradation studies indicate that reduced catabolism of FN may account for significant elevations in cells and sera. DMD sera cultured on control fibroblasts caused metabolic alterations reminiscent of dystrophic cells (increased FN and collagen accumulation, decreased RNA synthesis). Many of the observed metabolic changes are age-related in DMD, increasing in older patients. These results suggest that overproduction by fibroblasts and increased serum levels of components of the ECM in DMD may influence the accumulation of connective tissue in DMD muscle. DMD may not be of myopathic origin but an increased compartment of fibroblasts and macrophages as observed in DMD muscle may result from chemotactic mobilization caused by elevated FN and/or collagen in the tissue.