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Rab-small GTPases are involved in fluvastatin and pravastatin-induced vacuolation in rat skeletal myofibers

Kazuho Sakamoto^*,1, Takashi Honda, Sachihiko Yokoya, Satoshi Waguri^¶ and Junko Kimura^*

Departments of
^* Pharmacology,

Cell Science,

^¶ Anatomy and Histology, School of Medicine, and

Department of Human Life Sciences, School of Nursing, Fukushima Medical University, Fukushima, Japan

¹Correspondence: Department of Pharmacology, School of Medicine, Fukushima Medical University, Hikarigaoka 1, Fukushima 960-1295, Japan. E-mail: kazuho{at}fmu.ac.jp

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.—Sakamoto, K., Honda, T., Yokoya, S., Waguri, S., Kimura, J. Rab-small GTPases are involved in fluvastatin and pravastatin-induced vacuolation in rat skeletal myofibers.

Key Words: HMG-CoA reductase inhibitors • isoprenylation • myopathy • rhabdomyolysis • skeletal muscle