Clofibrate-induced apoptosis is mediated by Ca2+-dependent caspase-12 activation.
The mechanism of fibrate-induced myopathy was investigated in this report. When clofibrate (30 to 300 microM) was applied to L6 rat skeletal myoblasts, dose-dependently apoptosis was observed within 24 h. In the apoptotic myoblasts, a caspase-12 cleavage was observed at 2 h and with following caspases-9 and -3-related cascade activation. In contrast, the neutral protease calpain, that is a key enzyme in ER stress-related apoptosis via caspase-12 activation, was significantly decreased during apoptosis. Next, the authors evaluated a role of calcium-dependent signal(s). When clofibrate was added into medium, cytosolic calcium concentration was rapidly and persistently increased. On the other hand, an addition of 10 mM EGTA depressed sustained calcium phase, and concurrent myoblasts apoptosis was completely inhibited. Taken together, our findings indicate that the clofibrate-induced myopathy is triggered by Ca2+ influx, then activated cytosolic caspase-12 through calpain-independent cascade, and consequently caused apoptotic DNA fragmentation.
Matzno
Sumio
S
First Department of Biochemistry, School of Pharmaceutical Sciences, Mukogawa Women's University, 11-68, Koshien, Nishinomiya, Hyogo 663-8179, Japan. smatzno@mwu.mukogawa-u.ac.jp
Yasuda
Shinya
S
Kitada
Yuka
Y
Akiyoshi
Takeshi
T
Tanaka
Naoko
N
Juman
Sachiko
S
Shinozuka
Kazumasa
K
Nakabayashi
Toshikatsu
T
Matsuyama
Kenji
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000494:pharmacology*; D002154:Calpain / Q000494:pharmacology; D053454:Caspase 12; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D002994:Clofibrate / Q000494:pharmacology*; D003600:Cytosol / Q000201:enzymology; D004533:Egtazic Acid / Q000494:pharmacology; D004789:Enzyme Activation; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats
D002614:Chelating Agents; D000960:Hypolipidemic Agents; D004533:Egtazic Acid; D002154:Calpain; C506443:Casp12 protein, rat; C505410:Casp3 protein, rat; C506435:Casp9 protein, rat; D053454:Caspase 12; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D002994:Clofibrate; D002118:Calcium