C/EBP homologous protein deficiency inhibits statin-induced myotoxicity.


Department of Pharmacology and Smart-Aging Convergence Research Center, 317-1 Daemyung-dong, Daegu, Republic of Korea. Electronic address: [Email]


It has been well established that HMG-CoA reductase inhibitors (statins) cause adverse side effects in skeletal muscle ranging from mild to fatal myotoxicity upon dose, drug interaction, and exercise. However, the underlying mechanisms by which statins induce myotoxicity have not been fully addressed. Recent reports showed that statins induce endoplasmic reticulum (ER) stress and cell death in immune cells and myoblasts in vitro. Therefore, the goal of study is to investigate the molecular mechanism by which statins induce skeletal muscle cell death and myopathy via the regulation of ER stress. Biochemical data showed that TUDCA, an ER stress inhibitor, inhibited atorvastatin- and simvastatin-induced protein cleavages of PARP-1 and caspase-3, respectively. Actually, statin treatment activated marker proteins of unfolded protein responses (UPR) including ATF6, CHOP, and spliced XBP1 and these responses were inhibited by TUDCA. In addition, statin treatment induced mRNA levels of UPR marker genes, suggesting that statins activate ER stress in a transcriptional regulation. The physiological relevance of ER stress in statin-induced myopathy was demonstrated in a mouse model of myopathy, in which instillation of simvastatin and atorvastatin led to myopathy. Notably, the reduction of muscular endurance in response to statin instillation was significantly improved in TUDCA treating group compared to vehicle control group. Moreover, CHOP deficiency mice showed restoration of statin-induced reduction of muscular endurance, suggesting that statin induces myopathy via ER stress and in a CHOP-dependent manner. Taken together, these findings indicate that statins specifically induce myopathy in an ER stress-dependent manner, suggesting the therapeutic potential of ER stress regulation in preventing adverse effects of statin.