Mechanism of Statin-Induced Contractile Dysfunction in Rat Cultured Skeletal Myofibers
Abstract.: An adverse effect of statins, cholesterol-lowering drugs, is contractile dysfunction of skeletal muscles. We investigated the mechanism underlying this effect in cultured myofibers isolated from rats. Fluvastatin (Flv) for 72 h decreased caffeine- and ionomycin-induced contraction of myof...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2010-01-01
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| Series: | Journal of Pharmacological Sciences |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1347861319308230 |
| _version_ | 1828407819294998528 |
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| author | Syoko Tanaka Kazuho Sakamoto Masaya Yamamoto Anna Mizuno Tomoyuki Ono Satoshi Waguri Junko Kimura |
| author_facet | Syoko Tanaka Kazuho Sakamoto Masaya Yamamoto Anna Mizuno Tomoyuki Ono Satoshi Waguri Junko Kimura |
| author_sort | Syoko Tanaka |
| collection | DOAJ |
| description | Abstract.: An adverse effect of statins, cholesterol-lowering drugs, is contractile dysfunction of skeletal muscles. We investigated the mechanism underlying this effect in cultured myofibers isolated from rats. Fluvastatin (Flv) for 72 h decreased caffeine- and ionomycin-induced contraction of myofibers and Ca2+ release from sarcoplasmic reticulum (SR). Ca2+-shortening curves measured in skinned myofibers indicated that myofibrillar Ca2+ sensitivity was unaffected by Flv. A luciferin–luciferase assay revealed less ATP contents in Flv-treated myofibers. Among mevalonate metabolites, including geranylgeranylpyrophosphate (GGPP), farnesylpyrophosphate (FPP), coenzyme Q9, and coenzyme Q10, only GGPP prevented Flv-induced ATP reduction. A selective Rab geranylgeranyltransferase (GG transferase) inhibitor, perillyl alcohol (POH), and a specific GG transferase-I inhibitor, GGTI-298, both mimicked Flv in decreasing ATP and contraction. Mitochondrial membrane potential was decreased by Flv, and this effect was rescued by GGPP and mimicked by POH and GGTI-298. An endoplasmic reticulum (ER)-to-Golgi traffic inhibitor, brefeldin A, and a Rho inhibitor, membrane permeable exoenzyme C3 transferase, both decreased ATP. We conclude that statin-induced contractile dysfunction is due to reduced Ca2+ release from SR and reduced ATP levels in myofibers with damaged mitochondria. GGPP depletion and subsequent inactivation of Rab1, possibly along with Rho, may underlie the mitochondrial damage by Flv. Keywords:: statin, skeletal muscle, prenylation, mitochondria, autophagy |
| first_indexed | 2024-12-10T11:30:04Z |
| format | Article |
| id | doaj.art-930c19f642824baa883f36303472b096 |
| institution | Directory Open Access Journal |
| issn | 1347-8613 |
| language | English |
| last_indexed | 2024-12-10T11:30:04Z |
| publishDate | 2010-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Pharmacological Sciences |
| spelling | doaj.art-930c19f642824baa883f36303472b0962022-12-22T01:50:37ZengElsevierJournal of Pharmacological Sciences1347-86132010-01-011144454463Mechanism of Statin-Induced Contractile Dysfunction in Rat Cultured Skeletal MyofibersSyoko Tanaka0Kazuho Sakamoto1Masaya Yamamoto2Anna Mizuno3Tomoyuki Ono4Satoshi Waguri5Junko Kimura6Departments of Pharmacology, 1 Hikarigaoka, Fukushima 960-1295, JapanDepartments of Pharmacology, 1 Hikarigaoka, Fukushima 960-1295, Japan; Corresponding author. kazuho@fmu.ac.jpAnatomy and Histology, School of Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295, JapanDepartments of Pharmacology, 1 Hikarigaoka, Fukushima 960-1295, JapanDepartments of Pharmacology, 1 Hikarigaoka, Fukushima 960-1295, JapanAnatomy and Histology, School of Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295, JapanDepartments of Pharmacology, 1 Hikarigaoka, Fukushima 960-1295, JapanAbstract.: An adverse effect of statins, cholesterol-lowering drugs, is contractile dysfunction of skeletal muscles. We investigated the mechanism underlying this effect in cultured myofibers isolated from rats. Fluvastatin (Flv) for 72 h decreased caffeine- and ionomycin-induced contraction of myofibers and Ca2+ release from sarcoplasmic reticulum (SR). Ca2+-shortening curves measured in skinned myofibers indicated that myofibrillar Ca2+ sensitivity was unaffected by Flv. A luciferin–luciferase assay revealed less ATP contents in Flv-treated myofibers. Among mevalonate metabolites, including geranylgeranylpyrophosphate (GGPP), farnesylpyrophosphate (FPP), coenzyme Q9, and coenzyme Q10, only GGPP prevented Flv-induced ATP reduction. A selective Rab geranylgeranyltransferase (GG transferase) inhibitor, perillyl alcohol (POH), and a specific GG transferase-I inhibitor, GGTI-298, both mimicked Flv in decreasing ATP and contraction. Mitochondrial membrane potential was decreased by Flv, and this effect was rescued by GGPP and mimicked by POH and GGTI-298. An endoplasmic reticulum (ER)-to-Golgi traffic inhibitor, brefeldin A, and a Rho inhibitor, membrane permeable exoenzyme C3 transferase, both decreased ATP. We conclude that statin-induced contractile dysfunction is due to reduced Ca2+ release from SR and reduced ATP levels in myofibers with damaged mitochondria. GGPP depletion and subsequent inactivation of Rab1, possibly along with Rho, may underlie the mitochondrial damage by Flv. Keywords:: statin, skeletal muscle, prenylation, mitochondria, autophagyhttp://www.sciencedirect.com/science/article/pii/S1347861319308230 |
| spellingShingle | Syoko Tanaka Kazuho Sakamoto Masaya Yamamoto Anna Mizuno Tomoyuki Ono Satoshi Waguri Junko Kimura Mechanism of Statin-Induced Contractile Dysfunction in Rat Cultured Skeletal Myofibers Journal of Pharmacological Sciences |
| title | Mechanism of Statin-Induced Contractile Dysfunction in Rat Cultured Skeletal Myofibers |
| title_full | Mechanism of Statin-Induced Contractile Dysfunction in Rat Cultured Skeletal Myofibers |
| title_fullStr | Mechanism of Statin-Induced Contractile Dysfunction in Rat Cultured Skeletal Myofibers |
| title_full_unstemmed | Mechanism of Statin-Induced Contractile Dysfunction in Rat Cultured Skeletal Myofibers |
| title_short | Mechanism of Statin-Induced Contractile Dysfunction in Rat Cultured Skeletal Myofibers |
| title_sort | mechanism of statin induced contractile dysfunction in rat cultured skeletal myofibers |
| url | http://www.sciencedirect.com/science/article/pii/S1347861319308230 |
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