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Proteasomes in distal myopathy with rimmed vacuoles
T Kumamoto1, S Fujimoto, S Nagao
1Third Department of Internal Medicine, Oita Medical University, Hasama.
Abstract:
In a previous report we suggested that muscle fibers in distal myopathy with rimmed vacuoles (DMRV) were degraded by both lysosomal proteolysis (cathepsins) and Ca2+-dependent, nonlysosomal proteolysis (calpain). Given recent evidence of abnormal ubiquitin accumulation in rimmed vacuoles, we examined the role of the ATP-ubiquitin-dependent proteolytic pathway (proteasomes) in myofiber degradation in this myopathy. Immunohistochemically, proteasomes (26S) were located in the cytoplasm in normal human muscle, but the staining intensity was weak. Quantitative analysis showed more reactivity for proteasomes in DMRV muscles and, to a lesser extent, in muscles from muscular dystrophy, polymyositis, and amyotrophic lateral sclerosis patients. In DMRV, proteasomes often were located within or on the rim of rimmed vacuoles, and in the cytoplasm of atrophic fibers. Ubiquitin accumulation was marked within rimmed vacuoles and was seen less extensively in the cytoplasm of atrophic fibers. The latter proteins colocalized well. In other diseased muscles, proteasomes and ubiquitin showed a positive reaction in the atrophic or necrotic fibers. The results indicate increased proteasome and ubiquitin in these muscle fibers as well as in other diseased muscle fibers. We suggest that the ATP-ubiquitin-proteasome proteolytic pathway as well as the nonlysosomal calpain and the lysosomal proteolytic pathway may participate in the muscle fiber degradation in DMRV.
Insights
Distal myopathy with rimmed vacuoles (DMRV) involves muscle fiber degradation via lysosomal, calpain, and ATP-ubiquitin-proteasome pathways. Increased proteasome and ubiquitin activity are key indicators in DMRV and other muscle diseases.
Area of Science:
- Muscle Physiology and Pathology
- Cellular Degradation Pathways
Background:
- Previous studies implicated lysosomal (cathepsins) and Ca2+-dependent (calpain) proteolysis in distal myopathy with rimmed vacuoles (DMRV).
- Abnormal ubiquitin accumulation observed in rimmed vacuoles suggests a potential role for the ubiquitin-proteasome system.
Purpose of the Study:
- To investigate the involvement of the ATP-ubiquitin-dependent proteolytic pathway (proteasomes) in myofiber degradation in DMRV.
- To compare proteasome and ubiquitin expression in DMRV with other muscle diseases.
Main Methods:
- Immunohistochemical analysis of proteasome (26S) and ubiquitin localization in muscle biopsies.
- Quantitative analysis of proteasome reactivity in DMRV, muscular dystrophy, polymyositis, and amyotrophic lateral sclerosis.
- Assessment of co-localization of proteasomes and ubiquitin in affected muscle fibers.
Main Results:
- Proteasomes showed increased reactivity in DMRV muscles compared to normal muscle, with localization within or on the rim of vacuoles and in atrophic fibers.
- Marked ubiquitin accumulation was observed within rimmed vacuoles and in atrophic fibers in DMRV, co-localizing with proteasomes.
- Increased proteasome and ubiquitin expression was also noted in atrophic or necrotic fibers of other diseased muscles.
Conclusions:
- The ATP-ubiquitin-proteasome pathway, alongside calpain and lysosomal pathways, likely contributes to muscle fiber degradation in DMRV.
- Elevated proteasome and ubiquitin levels are characteristic of muscle fiber pathology in DMRV and other neuromuscular disorders.