Inhibition of cholesterol biosynthesis by squalene epoxidase inhibitor avoids apoptotic cell death in L6 myoblasts
The relationship between the inhibition of cholesterol biosynthesis and occurrence of myopathy was studied in L6 myoblasts using two lines of cholesterol biosynthesis inhibitors, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (simvastatin) and squalene epoxidase inhibitors (TU-2...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
1997-08-01
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| Series: | Journal of Lipid Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520371820 |
| _version_ | 1818827669721055232 |
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| author | S Matzno T Yamauchi M Gohda N Ishida K Katsuura Y Hanasaki T Tokunaga H Itoh N Nakamura |
| author_facet | S Matzno T Yamauchi M Gohda N Ishida K Katsuura Y Hanasaki T Tokunaga H Itoh N Nakamura |
| author_sort | S Matzno |
| collection | DOAJ |
| description | The relationship between the inhibition of cholesterol biosynthesis and occurrence of myopathy was studied in L6 myoblasts using two lines of cholesterol biosynthesis inhibitors, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (simvastatin) and squalene epoxidase inhibitors (TU-2078 and NB-598). All inhibitors completely inhibited the cholesterol synthesis in L6 myoblasts at doses of 1 and 3 microM. Simvastatin (3 microM) inhibited the fusion reaction of L6 myoblasts followed by the severe cellular damage. The myoblasts also had failed actin fiber formation and creatinine phosphokinase (CPK) production. Additionally, this agent also caused apoptotic cell death in differentiated L6 muscle fiber, indicating that skeletal myopathy by HMG-CoA reductase inhibitors seems to occur not only in differentiating immature myoblasts but also in matured skeletal myotubes. In contrast, TU-2078 and NB-598 had no effect on the fusion reaction of differentiating myoblasts or on the cellular viability of muscle fiber at 3 microM, enough to completely inhibit cholesterol biosynthesis. It is conceivable that the mevalonate depletion and subsequent failure of ras farnesylation induced by simvastatin might cause the defects in differentiation and maintenance of the muscle fiber. Squalene epoxidase inhibitors did not show this adverse effect presumably because of the enzyme inhibition downstream of farnesyl synthesis. The present findings suggest the safe use of squalene epoxidase inhibitors in lipid-lowering therapy. |
| first_indexed | 2024-12-19T00:47:14Z |
| format | Article |
| id | doaj.art-6cc5d74f3122401d9ec4fb054580e92b |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-19T00:47:14Z |
| publishDate | 1997-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-6cc5d74f3122401d9ec4fb054580e92b2022-12-21T20:44:14ZengElsevierJournal of Lipid Research0022-22751997-08-0138816391648Inhibition of cholesterol biosynthesis by squalene epoxidase inhibitor avoids apoptotic cell death in L6 myoblastsS Matzno0T Yamauchi1M Gohda2N Ishida3K Katsuura4Y Hanasaki5T Tokunaga6H Itoh7N Nakamura8Research Division, The Green Cross Corporation, Hirakata, Osaka, Japan.Research Division, The Green Cross Corporation, Hirakata, Osaka, Japan.Research Division, The Green Cross Corporation, Hirakata, Osaka, Japan.Research Division, The Green Cross Corporation, Hirakata, Osaka, Japan.Research Division, The Green Cross Corporation, Hirakata, Osaka, Japan.Research Division, The Green Cross Corporation, Hirakata, Osaka, Japan.Research Division, The Green Cross Corporation, Hirakata, Osaka, Japan.Research Division, The Green Cross Corporation, Hirakata, Osaka, Japan.Research Division, The Green Cross Corporation, Hirakata, Osaka, Japan.The relationship between the inhibition of cholesterol biosynthesis and occurrence of myopathy was studied in L6 myoblasts using two lines of cholesterol biosynthesis inhibitors, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (simvastatin) and squalene epoxidase inhibitors (TU-2078 and NB-598). All inhibitors completely inhibited the cholesterol synthesis in L6 myoblasts at doses of 1 and 3 microM. Simvastatin (3 microM) inhibited the fusion reaction of L6 myoblasts followed by the severe cellular damage. The myoblasts also had failed actin fiber formation and creatinine phosphokinase (CPK) production. Additionally, this agent also caused apoptotic cell death in differentiated L6 muscle fiber, indicating that skeletal myopathy by HMG-CoA reductase inhibitors seems to occur not only in differentiating immature myoblasts but also in matured skeletal myotubes. In contrast, TU-2078 and NB-598 had no effect on the fusion reaction of differentiating myoblasts or on the cellular viability of muscle fiber at 3 microM, enough to completely inhibit cholesterol biosynthesis. It is conceivable that the mevalonate depletion and subsequent failure of ras farnesylation induced by simvastatin might cause the defects in differentiation and maintenance of the muscle fiber. Squalene epoxidase inhibitors did not show this adverse effect presumably because of the enzyme inhibition downstream of farnesyl synthesis. The present findings suggest the safe use of squalene epoxidase inhibitors in lipid-lowering therapy.http://www.sciencedirect.com/science/article/pii/S0022227520371820 |
| spellingShingle | S Matzno T Yamauchi M Gohda N Ishida K Katsuura Y Hanasaki T Tokunaga H Itoh N Nakamura Inhibition of cholesterol biosynthesis by squalene epoxidase inhibitor avoids apoptotic cell death in L6 myoblasts Journal of Lipid Research |
| title | Inhibition of cholesterol biosynthesis by squalene epoxidase inhibitor avoids apoptotic cell death in L6 myoblasts |
| title_full | Inhibition of cholesterol biosynthesis by squalene epoxidase inhibitor avoids apoptotic cell death in L6 myoblasts |
| title_fullStr | Inhibition of cholesterol biosynthesis by squalene epoxidase inhibitor avoids apoptotic cell death in L6 myoblasts |
| title_full_unstemmed | Inhibition of cholesterol biosynthesis by squalene epoxidase inhibitor avoids apoptotic cell death in L6 myoblasts |
| title_short | Inhibition of cholesterol biosynthesis by squalene epoxidase inhibitor avoids apoptotic cell death in L6 myoblasts |
| title_sort | inhibition of cholesterol biosynthesis by squalene epoxidase inhibitor avoids apoptotic cell death in l6 myoblasts |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520371820 |
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