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Rab‐small GTPases are involved in fluvastatin and pravastatin‐induced vacuolation in rat skeletal myofibers
Author(s) -
Sakamoto Kazuho,
Honda Takashi,
Yokoya Sachihiko,
Waguri Satoshi,
Kimura Junko
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.07-8713com
Subject(s) - rab , fluvastatin , skeletal muscle , chemistry , pravastatin , intracellular , myotoxin , biochemistry , pharmacology , endocrinology , medicine , microbiology and biotechnology , biology , gtpase , phospholipase a2 , enzyme , simvastatin , cholesterol
Three‐hydroxy‐3methyl‐gutaryl‐CoA (HMG‐CoA) reductase inhibitors, known as statins, induce skeletal muscle injury including myalgia, myositis, and rhabdo‐myolysis. 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 prav‐astatin 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 geranylgeranylpyro‐phosphate (GGPP) with fluvastatin prevented the morphological changes, while that of farnesylpyrophos‐phate (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 intracel‐lular 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 fluva‐statin and pravastatin‐induced vacuolation in rat skeletal myofibers. FASEB J . 21, 4087–4094 (2007)