Mechanisms of simvastatin myotoxicity: The role of autophagy flux inhibition.

Authors

Arya Emami, University of Manitoba
Shahla Shojaei, University of Manitoba
Simone C. da Silva Rosa, University of Manitoba; Children's Hospital Research Institute of Manitoba
Mahmoud Aghaei, University of Manitoba; Isfahan University of Medical Sciences
Ehsan Samiei, University of Victoria
Amir Reza Vosoughi, University of Manitoba
Forouh Kalantari, University of Manitoba
Philip Kawalec, University of Manitoba
James Thliveris, University of Manitoba
Pawan Sharma, Thomas Jefferson UniversityFollow
Amir A. Zeki, University of California, Davis; Veterans Affairs Medical Center; Center for Comparative Respiratory Biology and Medicine
Mohsen Akbari, University of Victoria
Joseph W. Gordon, University of Manitoba; Children's Hospital Research Institute of Manitoba
Saeid Ghavami, University of Manitoba; Center for Comparative Respiratory Biology and Medicine; Children's Hospital Research Institute of Manitoba; Shiraz University of Medical Science

Document Type

Article

Publication Date

8-23-2019

Comments

This article is the author’s final published version in European Journal of Pharmacology, Volume 862, November 2019, Article number 172616.

The published version is available at https://doi.org/10.1016/j.ejphar.2019.172616. Copyright © Emami et al.

Abstract

Statins are some of the most widely used drugs worldwide, but one of their major side effects is myotoxicity. Using mouse myoblast (C2C12) and human alveolar rhabdomyosarcoma cell lines (RH30) in both 2-dimensional (2D) and 3-dimensional (3D) cell culture, we investigated the mechanisms of simvastatin's myotoxicity. We found that simvastatin significantly reduced cell viability in C2C12 cells compared to RH30 cells. However, simvastatin induced greater apoptosis in RH30 compared to C2C12 cells. Simvastatin-induced cell death is dependent on geranylgeranyl pyrophosphate (GGPP) in C2C12 cells, while in RH30 cells it is dependent on both farnesyl pyrophosphate (FPP) and GGPP. Simvastatin inhibited autophagy flux in both C2C12 and RH30 cells and inhibited lysosomal acidification in C2C12 cells, while autophagy inhibition with Bafilomycin-A1 increased simvastatin myotoxicity in both cell lines. Simvastatin induced greater cell death in RH30 cells compared to C2C12 in a 3D culture model with similar effects on autophagy flux as in 2D culture. Overall, our results suggest that simvastatin-induced myotoxicity involves both apoptosis and autophagy, where autophagy serves a pro-survival role in both cell lines. The sensitivity to simvastatin-induced myotoxicity differs between 2D and 3D culture, demonstrating that the cellular microenvironment is a critical factor in regulating simvastatin-induced cell death in myoblasts.

Recommended Citation

Emami, Arya; Shojaei, Shahla; da Silva Rosa, Simone C.; Aghaei, Mahmoud; Samiei, Ehsan; Vosoughi, Amir Reza; Kalantari, Forouh; Kawalec, Philip; Thliveris, James; Sharma, Pawan; Zeki, Amir A.; Akbari, Mohsen; Gordon, Joseph W.; and Ghavami, Saeid, "Mechanisms of simvastatin myotoxicity: The role of autophagy flux inhibition." (2019). Center for Translational Medicine Faculty Papers. Paper 63.
https://jdc.jefferson.edu/transmedfp/63

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

PubMed ID

31449810

Language

English