Fenofibrate-induced muscular toxicity is associated with a metabolic shift limited to type-1 muscles in rats.
Morphological changes and mRNA expression levels in type-1 predominant soleus and type-2 predominant tensor fasciae latae muscles of rats treated with fenofibrate were investigated. After fenofibrate by oral gavage at 300 mg/kg/day for 28 days, degeneration/necrosis and regeneration of muscle fibers, cellular infiltration, and fibrosis were seen in soleus muscle. Additionally, expression of PDK4, CPT1-M, CPT2, and FACO mRNAs was increased. In contrast, no morphological changes or mRNA induction were apparent in tensor fasciae latae muscle. These data suggest that sensitivity to fenofibrate-induced muscle toxicity differs among muscles, with only type-1 fibers being susceptible. The up-regulation of PDK4, CPTs and FACO mRNA expression in soleus muscle indicates that the energy source is switched from glucose to fatty acids, and this might be related to the observed fenofibrate-induced muscular toxicity.
Okada
Miyoko
M
Safety Research Laboratory, Mitsubishi Tanabe Pharma Corporation, 1-1-1, Kazusakamatari, Kisarazu, Chiba 292-0818, Japan. Okada.Miyoko@mg.mt-pharma.co.jp
Sano
Fumiko
F
Ikeda
Itsuko
I
Sugimoto
Jiro
J
Takagi
Shiro
S
Sakai
Hiroki
H
Yanai
Tokuma
T
D000818:Animals; D003627:Data Interpretation, Statistical; D011345:Fenofibrate / Q000008:administration & dosage / Q000633:toxicity*; D005355:Fibrosis / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000633:toxicity*; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009336:Necrosis / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D036401:Toxicity Tests, Chronic
D000960:Hypolipidemic Agents; D012333:RNA, Messenger; D005947:Glucose; D011345:Fenofibrate