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C/EBP homologous protein deficiency inhibits statin-induced myotoxicity

Title
C/EBP homologous protein deficiency inhibits statin-induced myotoxicity
Authors
Kim, Won HoLee, Chi-HoHan, Jung-HwaKim, SujinKim, Seong YongLim, Jae HyangPark, Kwon MooShin, Duk SeopWoo, Chang-Hoon
Ewha Authors
임재향
SCOPUS Author ID
임재향scopus
Issue Date
2019
Journal Title
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
ISSN
0006-291XJCR Link

1090-2104JCR Link
Citation
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS vol. 508, no. 3, pp. 857 - 863
Keywords
StatinCHOPmyopathyER stress
Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
Indexed
SCIE; SCOPUS WOS scopus
Document Type
Article
Abstract
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. (C) 2018 Elsevier Inc. All rights reserved.
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DOI
10.1016/j.bbrc.2018.11.166
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의과대학 > 의학과 > Journal papers
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