Simvastatin Suppresses the Differentiation of C2C12 Myoblast Cells Via a Rac Pathway

Overview

Journal J Muscle Res Cell Motil

Specialties Cell Biology
Physiology

Date 2008 Sep 17

PMID 18792797

Citations 10

Authors

Tomomi T Baba

Takayuki K Nemoto

Toshihiro Miyazaki

Shinichiro Oida

Affiliations

Soon will be listed here.

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.

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References

Pedersen T . Statin trials and goals of cholesterol-lowering therapy after AMI. Am Heart J. 1999; 138(2 Pt 2):S177-82. DOI: 10.1016/s0002-8703(99)70340-6. View

Madonna R, Di Napoli P, Massaro M, Grilli A, Felaco M, De Caterina A . Simvastatin attenuates expression of cytokine-inducible nitric-oxide synthase in embryonic cardiac myoblasts. J Biol Chem. 2005; 280(14):13503-11. DOI: 10.1074/jbc.M411859200. View

Hebert P, Gaziano J, Chan K, Hennekens C . Cholesterol lowering with statin drugs, risk of stroke, and total mortality. An overview of randomized trials. JAMA. 1997; 278(4):313-21. View

Maeda T, Matsunuma A, Kurahashi I, Yanagawa T, Yoshida H, Horiuchi N . Induction of osteoblast differentiation indices by statins in MC3T3-E1 cells. J Cell Biochem. 2004; 92(3):458-71. DOI: 10.1002/jcb.20074. View

Yaffe D, Saxel O . Serial passaging and differentiation of myogenic cells isolated from dystrophic mouse muscle. Nature. 1977; 270(5639):725-7. DOI: 10.1038/270725a0. View

Lacoste L, Lam J, Hung J, Letchacovski G, Solymoss C, Waters D . Hyperlipidemia and coronary disease. Correction of the increased thrombogenic potential with cholesterol reduction. Circulation. 1995; 92(11):3172-7. DOI: 10.1161/01.cir.92.11.3172. View

Yamasaki K, Sasaki T, Nemoto M, Eto Y, Tajima N . Differentiation-induced insulin secretion from nonendocrine cells with engineered human proinsulin cDNA. Biochem Biophys Res Commun. 1999; 265(2):361-5. DOI: 10.1006/bbrc.1999.1698. View

Matzno S, Yasuda S, Juman S, Yamamoto Y, Nagareya-Ishida N, Tazuya-Murayama K . Statin-induced apoptosis linked with membrane farnesylated Ras small G protein depletion, rather than geranylated Rho protein. J Pharm Pharmacol. 2005; 57(11):1475-84. DOI: 10.1211/jpp.57.11.0014. View

Jamal S, Eisenberg M, Christopoulos S . Rhabdomyolysis associated with hydroxymethylglutaryl-coenzyme A reductase inhibitors. Am Heart J. 2004; 147(6):956-65. DOI: 10.1016/j.ahj.2003.12.037. View

10.

Sidera C, Parsons R, Austen B . The regulation of beta-secretase by cholesterol and statins in Alzheimer's disease. J Neurol Sci. 2005; 229-230:269-73. DOI: 10.1016/j.jns.2004.11.044. View

11.

Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann D, Keller P . Simvastatin strongly reduces levels of Alzheimer's disease beta -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci U S A. 2001; 98(10):5856-61. PMC: 33303. DOI: 10.1073/pnas.081620098. View

12.

Sugiyama M, Kodama T, Konishi K, Abe K, Asami S, Oikawa S . Compactin and simvastatin, but not pravastatin, induce bone morphogenetic protein-2 in human osteosarcoma cells. Biochem Biophys Res Commun. 2000; 271(3):688-92. DOI: 10.1006/bbrc.2000.2697. View

13.

Zhang F, Casey P . Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem. 1996; 65:241-69. DOI: 10.1146/annurev.bi.65.070196.001325. View

14.

Turner N, Aley P, Hall K, Warburton P, Galloway S, Midgley L . Simvastatin inhibits TNFalpha-induced invasion of human cardiac myofibroblasts via both MMP-9-dependent and -independent mechanisms. J Mol Cell Cardiol. 2007; 43(2):168-76. DOI: 10.1016/j.yjmcc.2007.05.006. View

15.

Wozney J, Rosen V, Celeste A, Mitsock L, Whitters M, Kriz R . Novel regulators of bone formation: molecular clones and activities. Science. 1988; 242(4885):1528-34. DOI: 10.1126/science.3201241. View

16.

Ohnaka K, Shimoda S, Nawata H, Shimokawa H, Kaibuchi K, Iwamoto Y . Pitavastatin enhanced BMP-2 and osteocalcin expression by inhibition of Rho-associated kinase in human osteoblasts. Biochem Biophys Res Commun. 2001; 287(2):337-42. DOI: 10.1006/bbrc.2001.5597. View

17.

Katagiri T, Yamaguchi A, Komaki M, Abe E, Takahashi N, Ikeda T . Bone morphogenetic protein-2 converts the differentiation pathway of C2C12 myoblasts into the osteoblast lineage. J Cell Biol. 1994; 127(6 Pt 1):1755-66. PMC: 2120318. DOI: 10.1083/jcb.127.6.1755. View

18.

Kwak B, Mulhaupt F, Myit S, Mach F . Statins as a newly recognized type of immunomodulator. Nat Med. 2000; 6(12):1399-402. DOI: 10.1038/82219. View

19.

Sica D, Gehr T . Rhabdomyolysis and statin therapy: relevance to the elderly. Am J Geriatr Cardiol. 2002; 11(1):48-55. DOI: 10.1111/j.1076-7460.2002.01422.x. View

20.

Phillips B, Belmonte N, Vernochet C, Ailhaud G, Dani C . Compactin enhances osteogenesis in murine embryonic stem cells. Biochem Biophys Res Commun. 2001; 284(2):478-84. DOI: 10.1006/bbrc.2001.4987. View