| Project/Area Number |
20790210
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
General pharmacology
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| Research Institution | Fukushima Medical University |
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Principal Investigator |
SAKAMOTO Kazuho Fukushima Medical University, 医学部, 講師 (80433150)
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| Project Period (FY) |
2008 – 2009
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| Project Status |
Completed (Fiscal Year 2009)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2009: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2008: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | HMG-CoA還元酵素阻害薬 / 副作用 / 横紋筋融解症 / 低分子量G蛋白質 / 小胞輸送 / 蛋白質ゲラニルゲラニル化 / 骨格筋 / ミトコンドリア / トランスポーター / スタチン / 高脂血症 |
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| Research Abstract |
We investigated the mechanism behind the statin-induced adverse effects on skeletal muscle. (1) Fluvastatin inactivated Rab1 by inhibiting translocation of Rab1 from cytoplasm to sarcolemma in cultured myofibers. Brefeldin A, a specific inhibitor of ER-to-Golgi traffic, mimicked statin-induced vacuolation and cell death. Thus, we conclude that Rab1 inactivation is involved in statin-induced myofiber vacuolation and death. (2) We investigated the mechanism of statin-induced muscle weakness. Myofibers cultured with fluvastatin showed reduced contractility in response to caffeine, which stimulates Ca^<2+> release from sarcoplasmic reticulum. We also observed attenuation of Ca^<2+> release and ATP in statin-treated myofibers. GGPP supplementation with fluvastatin prevented ATP reduction, indicating that inactivation of small GTPases is also critical for the ATP reduction. (3) We examined drug transporters (Oatps) responsible for statin-induced myotoxicity. Skeletal myofibers were more sensitive to hydrophilic pravastatin and lipophilic fluvastatin than fibroblasts and myoblasts. RT-PCR analysis revealed that Oatp1a4/2b1, which take up statins into cells, are expressed in skeletal muscles. Therefore, I conclude that drug transporters in sarcolemma are necessary for the induction of myotoxicity by statins.
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