title: Simvastatin suppresses the differentiation of C2C12 myoblast cells via a Rac pathway.
abstract: Statins, which are known as cholesterol-lowering drugs, have several additional effects including the enhancement of bone formation and the stimulation of smooth muscle cell proliferation. In this study, we investigated the signal pathway of simvastatin operating in C2C12 myoblast cells. Myotube formation of C2C12 cells was efficiently blocked by 1 muM simvastatin, and mevalonic acid was able to cancel this effect. Geranylgeranyl pyrophosphate restored the myotube formation, whereas farnesyl pyrophosphate did not. These findings demonstrate that the Rho family, such as Rho, Rac and Cdc42, occurring downstream of geranylgeranyl pyrophosphate in the mevalonic acid pathway, was involved in the simvastatin-mediated blockage of myotube formation. An inhibitor of Rho kinase did not influence the myotube formation; whereas an inhibitor of Rac blocked this process. Taken together, we conclude that the differentiation of C2C12 cells into myotubes was blocked by simvastatin through the pathway mediated by Rac, not by Rho.
authors.affiliation: Department of Oral Molecular Biology, Unit of Basic Medical Sciences, Course of Medical and Dental Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8588, Japan. baba@nagasaki-u.ac.jp
authors.forename: Tomomi T
authors.initials: TT
authors.lastname: Baba
authors.forename: Takayuki K
authors.initials: TK
authors.lastname: Nemoto
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Oida
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018008:Myogenin / Q000235:genetics; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D012717:Sesquiterpenes / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology*; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: D000577:Amides; D000634:Aminoquinolines; C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018008:Myogenin; C487513:NSC 23766; D011106:Polyisoprenyl Phosphates; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011994:Recombinant Proteins; D012717:Sesquiterpenes; C108830:Y 27632; C004808:farnesyl pyrophosphate; D019821:Simvastatin; D054460:rho-Associated Kinases; D000469:Alkaline Phosphatase; D020744:rac GTP-Binding Proteins; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid
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