Sakamoto Kazuho, Honda Takashi, Yokoya Sachihiko, Waguri Satoshi, Kimura Junko
Department of Pharmacology, School of Medicine, Fukushima Medical University, Hikarigaoka 1, Fukushima 960-1295, Japan.
FASEB J. 2007 Dec;21(14):4087-94. doi: 10.1096/fj.07-8713com. Epub 2007 Jul 18.
Three-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors, known as statins, induce skeletal muscle injury including myalgia, myositis, and rhabdomyolysis. The mechanism of this myotoxicity remains unknown. This study examined the effect of statins on single skeletal myofibers enzymatically isolated from the rat flexor digitorum brevis muscles. Fluvastatin and pravastatin induced the formation of numerous vacuoles in the myofibers after 72 h of treatment. This effect progressed in a time- and concentration-dependent manner and, consequently, cell death occurred after 120 h. Electron micrographs revealed craters along the sarcolemma and swelling of the sarcoplasmic reticula and mitochondria, in addition to intracellular vacuoles. When caffeine was added after 72 h of fluvastatin treatment, contractile shortening of statin-treated myofibers was significantly attenuated and blebs formed on the surface of the myofibers. The coapplication of geranylgeranylpyrophosphate (GGPP) with fluvastatin prevented the morphological changes, while that of farnesylpyrophosphate (FPP) was ineffective. Furthermore, perillyl alcohol, an inhibitor of Rab geranylgeranyl transferase and geranylgeranyl transferase-I (GGTase-I), mimicked the effect of statins, while a specific GGTase-I inhibitor (GGTI-298) or a farnesyl transferase inhibitor (FTI-277) failed to do so. These results suggest that the inactivation of Rab GTPase, which involved in intracellular membrane transport, is a crucial factor in statin-induced-morphological abnormality in skeletal muscle fibers.
3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂，即他汀类药物，可引发骨骼肌损伤，包括肌痛、肌炎和横纹肌溶解。这种肌毒性的机制尚不清楚。本研究检测了他汀类药物对从大鼠趾短屈肌酶解分离出的单个骨骼肌纤维的影响。氟伐他汀和普伐他汀在处理72小时后可诱导肌纤维中形成大量空泡。这种效应呈时间和浓度依赖性进展，因此，120小时后发生细胞死亡。电子显微镜照片显示，除了细胞内空泡外，肌膜沿线有凹坑，肌浆网和线粒体肿胀。在氟伐他汀处理72小时后加入咖啡因时，他汀处理的肌纤维的收缩缩短明显减弱，并且在肌纤维表面形成气泡。香叶基香叶基焦磷酸（GGPP）与氟伐他汀共同应用可防止形态学变化，而法尼基焦磷酸（FPP）则无效。此外，紫苏醇是Rab香叶基香叶基转移酶和香叶基香叶基转移酶-I（GGTase-I）的抑制剂，可模拟他汀类药物的作用，而特异性GGTase-I抑制剂（GGTI-298）或法尼基转移酶抑制剂（FTI-277）则不能。这些结果表明，参与细胞内膜运输的Rab GTP酶失活是他汀类药物诱导骨骼肌纤维形态异常的关键因素。
