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Role of ubiquitin–proteasome proteolysis in muscle fiber destruction in experimental chloroquine‐induced myopathy
Author(s) -
Kimura Noriyuki,
Kumamoto Toshihide,
Oniki Takahiro,
Nomura Miwa,
Nakamura Kenichiro,
Abe Yoshitake,
Hazama Yusuke,
Ueyama Hidetsugu
Publication year - 2009
Publication title -
muscle and nerve
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.025
H-Index - 145
eISSN - 1097-4598
pISSN - 0148-639X
DOI - 10.1002/mus.21223
Subject(s) - ubiquitin , myopathy , proteolysis , proteasome , muscle atrophy , chloroquine , ubiquitin ligase , protein degradation , biology , vacuole , soleus muscle , endocrinology , medicine , skeletal muscle , microbiology and biotechnology , biochemistry , enzyme , immunology , cytoplasm , malaria , gene
Previous studies have documented the presence of rimmed vacuoles, atrophic fibers, and increased lysosomal cathepsin activity in skeletal muscle from animal models of chloroquine‐induced myopathy, suggesting that muscle fibers in this type of myopathy may be degraded via the lysosomal‐proteolysis pathway. Given recent evidence of abnormal ubiquitin accumulation in rimmed vacuoles, in this study we chose to examine the significance of the ubiquitin–proteasome proteolytic system in the process of muscle fiber destruction in experimental chloroquine myopathy. Expression of ubiquitin, 26S proteasome proteins, and ubiquitin ligases, such as muscle‐specific RING finger‐1 (MuRF‐1) and atrogin‐1/muscle atrophy F‐box protein (MAFbx), was analyzed in innervated and denervated rat soleus muscles after treatment with either saline or chloroquine. Abnormal accumulation of rimmed vacuoles was observed only in chloroquine‐treated denervated muscles. Ubiquitin and proteasome immunostaining, and ubiquitin, MuRF‐1, and atrogin‐1/MAFbx mRNAs were significantly increased in denervated soleus muscles from saline‐ and chloroquine‐treated rats when compared with contralateral innervated muscles. Further, ubiquitin and ubiquitin ligase mRNA levels were higher in denervated muscles from chloroquine‐treated rats when compared with saline‐treated rats. These data demonstrate increased proteasomes and ubiquitin in denervated muscles from chloroquine‐treated rats and suggest that the ubiquitin–proteasome proteolysis pathway as well as the lysosomal‐proteolysis pathway mediate muscle fiber destruction in experimental chloroquine myopathy. Muscle Nerve 39: 521–528, 2009