Proteasome expression in the skeletal muscles of patients with muscular dystrophy

Previous investigators have suggested that proteolysis by calpain, a Ca2+-d ependent protease, causes muscle fiber degradation in Duchenne and Becker m uscular dystrophies (DMD/BMD). Recent evidence indicates that the nonlysoso mal ATP-ubiquitin-dependent proteolytic complex (proteasomes) participates in muscle wasting during various catabolic states and in muscle fiber degra dation in physiological or pathological conditions. To elucidate the possib le role of proteasomes in dystrophic muscles, routine histochemistry and im munohistochemistry of 26S proteasomes were performed on muscle biopsy speci mens obtained from patients with various neuromuscular disorders including DMD/BMD, polymyositis (PM), amyotrophic lateral sclerosis, and peripheral n europathies, and on normal human muscle specimens. Immunohistochemically, p roteasomes were located in the cytoplasm in normal human muscle, but their staining intensity was faint. Compared to control muscles, abnormal increas es in both proteasomes and ubiquitin were demonstrated mainly in the cytopl asm of necrotic fibers and to a lesser extent in regenerative fibers in DMD /BMD and PM. Non-necrotic, atrophic fibers in all diseased muscles showed m oderate or weak immunoreactions for the proteins; their staining intensitie s were stronger than those of control muscle fibers. Both proteins often co localized well. Not all dystrophin-deficient muscle fibers showed a strong reaction for proteasomes. Our results showed increased proteasomes in necro tic and regenerative muscle fibers in DMD/ PMD, although this may not be di sease-specific up-regulation. We suggest that the ATP-ubiquitin-dependent p roteolytic pathway as well as the nonlysosomal calpain pathway may particip ate in muscle fiber degradation in muscular dystrophy.