• Noriyuki Kimura, Toshihide Kumamoto, Takahiro Oniki, Miwa Nomura, Kenichiro Nakamura, Yoshitake Abe, Yusuke Hazama, and Hidetsugu Ueyama.
• Department of Neurology and Neuromuscular Disorders, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama, Yufu, Oita 879-5593, Japan.
• Muscle Nerve. 2009 Apr 1; 39 (4): 521-8.

AbstractPrevious 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.

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