Studies on statin-induced myopathy in zebrafish

• Main Authors: Ming-Wu Feng, 馮明五
• Other Authors: Chang-Jen Huang
• Format: Others
• Language: zh-TW
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/73910123763687531956

碩士 === 國立臺灣大學 === 生化科學研究所 === 103 === HMG-CoA reductase inhibitors, also known as statins, are widely used to treat hypercholesterolemia. However, they can lead to a number of dose-dependent and muscle-associated side effects, ranging from myalgia to myositis and rhabdomyolysis. The frequency of rhabdomyolysis incidence is low, however, it is reported that concomitant use of Simvastatin with Rapamycin, an immunosuppressor which inhibits TOR (target of rapamycin) activity, in liver transplant patient resulted in severe rhabdomyolysis. In this study, we generated a zebrafish statin-induced myopathy model. At first, we compare the adverse effect induced by Simvastatin, Lovastatin and Atorvastatin in zebrafish. Then, we found that Simvastatin could induce visible muscle damage in zebrafish embryos, with degree of damage proportionate to Simvastatin concentration and length of exposure. We further investigated the effect of Rapamycin and Simvastatin co-treatment on zebrafish. Surprisingly, the results showed that the muscle toxicity induced by Simvastatin can be rescued by Rapamycin. To confirm this phenomenon is related to TOR signaling, we also knocked down the zebrafish TOR gene (ztor) using splicing morpholino. However, the morphants with reduced expression of TOR still demonstrated muscle damage upon Simvastatin administration, and the effect can be blocked by Rapamycin as well. These results indicate that Rapamycin may exert its protective effect against Simvastatin-induced myopathy via a TOR-independent mechanism.