{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:33:39Z","timestamp":1790613219442,"version":"4.1.0"},"reference-count":61,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2018,5,21]],"date-time":"2018-05-21T00:00:00Z","timestamp":1526860800000},"content-version":"vor","delay-in-days":140,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004569","name":"Ministerstwo Edukacji i Nauki","doi-asserted-by":"publisher","award":["05-1\/KNOW2\/2015"],"award-info":[{"award-number":["05-1\/KNOW2\/2015"]}],"id":[{"id":"10.13039\/501100004569","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["UMO-2013\/11\/B\/NZ5\/03106"],"award-info":[{"award-number":["UMO-2013\/11\/B\/NZ5\/03106"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Oxidative Medicine and Cellular Longevity"],"published-print":{"date-parts":[[2018,1]]},"abstract":"<jats:p>\n                    The present study investigated the cytotoxic effects of statins (atorvastatin (ATR) and simvastatin (SIM), resp.) and methyl\u2010beta\u2010cyclodextrin (M\n                    <jats:italic>\u03b2<\/jats:italic>\n                    CD), at their respective IC\n                    <jats:sub>50<\/jats:sub>\n                    concentrations, on muscle regeneration in the in vitro model of murine C2C12 myoblasts. Cotreatment with mevalonate (MEV), farnesol (FOH), geranylgeraniol (GGOH), or water\u2010soluble cholesterol (Chol\u2010PEG) was employed to determine whether the statin\u2010dependent myotoxicity resulted from the lower cholesterol levels or the attenuated synthesis of intermediates of mevalonate pathway. Our findings demonstrated that while GGOH fully reverted the statin\u2010mediated cell viability in proliferating myoblasts, Chol\u2010PEG exclusively rescued M\n                    <jats:italic>\u03b2<\/jats:italic>\n                    CD\u2010induced toxicity in myocytes. Statins caused loss of prenylated RAP1, whereas the GGOH\u2010dependent positive effect was accompanied by loss of nonprenylated RAP1. Geranylgeranyltransferases are essential for muscle cell survival as inhibition with GGTI\u2010286 could not be reversed by GGOH cotreatment. The increase in cell viability correlated with elevated AKT 1(S463) and GSK\u20103\n                    <jats:italic>\u03b2<\/jats:italic>\n                    (S9) phosphorylations. Slight increase in the levels of autophagy markers (Beclin 1, MAP LC\u20103IIb) was found in response to GGOH cotreatment. Autophagy rose time\u2010dependently during myogenesis and was inhibited by statins and M\n                    <jats:italic>\u03b2<\/jats:italic>\n                    CD. Statins and M\n                    <jats:italic>\u03b2<\/jats:italic>\n                    CD also suppressed myogenesis and neither nonsterol isoprenoids nor Chol\u2010PEG could reverse this effect. These results point to GGOH as the principal target of statin\u2010dependent myotoxicity, whereas plasma membrane cholesterol deposit is ultimately essential to restore viability of M\n                    <jats:italic>\u03b2<\/jats:italic>\n                    CD\u2010treated myocytes. Overall, this study unveils for the first time a link found between the GGOH\u2010 and Chol\u2010PEG\u2010dependent reversal of statin\u2010 or M\n                    <jats:italic>\u03b2<\/jats:italic>\n                    CD\u2010mediated myotoxicity and cytoprotective autophagy, respectively.\n                  <\/jats:p>","DOI":"10.1155\/2018\/6463807","type":"journal-article","created":{"date-parts":[[2018,5,21]],"date-time":"2018-05-21T19:31:25Z","timestamp":1526931085000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Geranylgeraniol Prevents Statin\u2010Dependent Myotoxicity in C2C12 Muscle Cells through RAP1 GTPase Prenylation and Cytoprotective Autophagy"],"prefix":"10.1155","volume":"2018","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1454-0852","authenticated-orcid":false,"given":"Anna","family":"Ja\u015bkiewicz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beata","family":"Paj\u0105k","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1115-733X","authenticated-orcid":false,"given":"Anna","family":"Litwiniuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8600-4130","authenticated-orcid":false,"given":"Kaja","family":"Urba\u0144ska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1307-2823","authenticated-orcid":false,"given":"Arkadiusz","family":"Orzechowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,5,21]]},"reference":[{"key":"e_1_2_8_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)41379-3"},{"key":"e_1_2_8_2_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.mol.0000191913.16321.60"},{"key":"e_1_2_8_3_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.45.120403.095748"},{"key":"e_1_2_8_4_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI0216421"},{"key":"e_1_2_8_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2003.10.033"},{"key":"e_1_2_8_6_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.07-8713com"},{"key":"e_1_2_8_7_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2009.00465.x"},{"key":"e_1_2_8_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2015.01.005"},{"key":"e_1_2_8_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/366643a0"},{"key":"e_1_2_8_10_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.62.070193.004223"},{"key":"e_1_2_8_11_2","doi-asserted-by":"publisher","DOI":"10.2174\/1568009610606010001"},{"key":"e_1_2_8_12_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.2001.81.1.153"},{"key":"e_1_2_8_13_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20080281"},{"key":"e_1_2_8_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.27.16409"},{"key":"e_1_2_8_15_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200317222"},{"key":"e_1_2_8_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2004.04.010"},{"key":"e_1_2_8_17_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1997.7145"},{"key":"e_1_2_8_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.56.5.1484"},{"key":"e_1_2_8_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/0012-1606(92)90066-P"},{"key":"e_1_2_8_20_2","doi-asserted-by":"publisher","DOI":"10.1006\/excr.1998.4284"},{"key":"e_1_2_8_21_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.107.6.1661"},{"key":"e_1_2_8_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)92815-2"},{"key":"e_1_2_8_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2010.01.056"},{"key":"e_1_2_8_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/270725a0"},{"key":"e_1_2_8_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1994.tb06459.x"},{"key":"e_1_2_8_26_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.195057"},{"key":"e_1_2_8_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"e_1_2_8_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2009.12.007"},{"key":"e_1_2_8_29_2","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2015.1100356"},{"key":"e_1_2_8_30_2","doi-asserted-by":"publisher","DOI":"10.4161\/auto.28448"},{"key":"e_1_2_8_31_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.08-128843"},{"key":"e_1_2_8_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2003.08.011"},{"key":"e_1_2_8_33_2","doi-asserted-by":"publisher","DOI":"10.1006\/taap.1995.1058"},{"key":"e_1_2_8_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(98)01320-9"},{"key":"e_1_2_8_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/0925-4439(95)00122-0"},{"key":"e_1_2_8_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.08.002"},{"key":"e_1_2_8_37_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0146726"},{"key":"e_1_2_8_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2015.04.010"},{"key":"e_1_2_8_39_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2008.164699"},{"key":"e_1_2_8_40_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M404838200"},{"key":"e_1_2_8_41_2","doi-asserted-by":"publisher","DOI":"10.1093\/glycob\/7.5.625"},{"key":"e_1_2_8_42_2","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2015.1115172"},{"key":"e_1_2_8_43_2","doi-asserted-by":"publisher","DOI":"10.1002\/bies.20558"},{"key":"e_1_2_8_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(01)02483-8"},{"key":"e_1_2_8_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203984"},{"key":"e_1_2_8_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/35073073"},{"key":"e_1_2_8_47_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0143777"},{"key":"e_1_2_8_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/33451"},{"key":"e_1_2_8_49_2","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvg180"},{"key":"e_1_2_8_50_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00550-14"},{"key":"e_1_2_8_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)37182-0"},{"key":"e_1_2_8_52_2","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00107.2011"},{"key":"e_1_2_8_53_2","doi-asserted-by":"publisher","DOI":"10.1002\/mus.22081"},{"key":"e_1_2_8_54_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-006-6235-z"},{"key":"e_1_2_8_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2011.10.449"},{"key":"e_1_2_8_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2007.02.049"},{"key":"e_1_2_8_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2012.01.008"},{"key":"e_1_2_8_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2005.10.108"},{"key":"e_1_2_8_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2006.02.043"},{"key":"e_1_2_8_60_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000190608.28704.71"},{"key":"e_1_2_8_61_2","doi-asserted-by":"publisher","DOI":"10.1002\/mus.20291"}],"container-title":["Oxidative Medicine and Cellular Longevity"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/downloads.hindawi.com\/journals\/omcl\/2018\/6463807.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/downloads.hindawi.com\/journals\/omcl\/2018\/6463807.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/2018\/6463807","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,7]],"date-time":"2024-08-07T06:55:33Z","timestamp":1723013733000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1155\/2018\/6463807"}},"subtitle":[],"editor":[{"given":"Christopher Horst","family":"Lillig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2018,1]]},"references-count":61,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2018,1]]}},"alternative-id":["10.1155\/2018\/6463807"],"URL":"https:\/\/doi.org\/10.1155\/2018\/6463807","archive":["Portico"],"relation":{},"ISSN":["1942-0900","1942-0994"],"issn-type":[{"value":"1942-0900","type":"print"},{"value":"1942-0994","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,1]]},"assertion":[{"value":"2017-09-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-01-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-05-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"6463807"}}