Role of ubiquitin-proteasome proteolysis in muscle fiber destruction in experimental chloroquine-induced myopathy.
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.
Kimura
Noriyuki
N
Department of Neurology and Neuromuscular Disorders, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama, Yufu, Oita 879-5593, Japan.
Kumamoto
Toshihide
T
Oniki
Takahiro
T
Nomura
Miwa
M
Nakamura
Kenichiro
K
Abe
Yoshitake
Y
Hazama
Yusuke
Y
Ueyama
Hidetsugu
H
D000818:Animals; D000962:Antimalarials / Q000633:toxicity; D002738:Chloroquine / Q000633:toxicity; D007150:Immunohistochemistry; D008297:Male; D009121:Muscle Denervation; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D009135:Muscular Diseases / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D012584:Sciatic Nerve; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
D000962:Antimalarials; D009124:Muscle Proteins; D012333:RNA, Messenger; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin; D002738:Chloroquine; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex