Mechanisms of simvastatin myotoxicity: The role of autophagy flux inhibition

Arya Emami, Shahla Shojaei, Simone C. da Silva Rosa, Mahmoud Aghaei, Ehsan Samiei, Amir Reza Vosoughi, Forouh Kalantari, Philip Kawalec, James Thliveris, Pawan Sharma, Amir Zeki, Mohsen Akbari, Joseph W. Gordon, Saeid Ghavami

    Research output: Contribution to journalArticle

    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.

    Original languageEnglish (US)
    Article number172616
    JournalEuropean Journal of Pharmacology
    Volume862
    DOIs
    StatePublished - Nov 5 2019

    Fingerprint

    Simvastatin
    Autophagy
    Cell Death
    Myoblasts
    Cell Line
    Alveolar Rhabdomyosarcoma
    Apoptosis
    Alveolar Epithelial Cells
    Cellular Microenvironment
    Hydroxymethylglutaryl-CoA Reductase Inhibitors
    Cell Survival
    Cell Culture Techniques

    Keywords

    • 3D culture model
    • Autophagy flux
    • Prenylation
    • Rhabdomyosarcoma
    • Statin

    ASJC Scopus subject areas

    • Pharmacology

    Cite this

    Emami, A., Shojaei, S., da Silva Rosa, S. C., Aghaei, M., Samiei, E., Vosoughi, A. R., ... Ghavami, S. (2019). Mechanisms of simvastatin myotoxicity: The role of autophagy flux inhibition. European Journal of Pharmacology, 862, [172616]. https://doi.org/10.1016/j.ejphar.2019.172616

    Mechanisms of simvastatin myotoxicity : The role of autophagy flux inhibition. / 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; Akbari, Mohsen; Gordon, Joseph W.; Ghavami, Saeid.

    In: European Journal of Pharmacology, Vol. 862, 172616, 05.11.2019.

    Research output: Contribution to journalArticle

    Emami, A, Shojaei, S, da Silva Rosa, SC, Aghaei, M, Samiei, E, Vosoughi, AR, Kalantari, F, Kawalec, P, Thliveris, J, Sharma, P, Zeki, A, Akbari, M, Gordon, JW & Ghavami, S 2019, 'Mechanisms of simvastatin myotoxicity: The role of autophagy flux inhibition', European Journal of Pharmacology, vol. 862, 172616. https://doi.org/10.1016/j.ejphar.2019.172616
    Emami A, Shojaei S, da Silva Rosa SC, Aghaei M, Samiei E, Vosoughi AR et al. Mechanisms of simvastatin myotoxicity: The role of autophagy flux inhibition. European Journal of Pharmacology. 2019 Nov 5;862. 172616. https://doi.org/10.1016/j.ejphar.2019.172616
    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 ; Akbari, Mohsen ; Gordon, Joseph W. ; Ghavami, Saeid. / Mechanisms of simvastatin myotoxicity : The role of autophagy flux inhibition. In: European Journal of Pharmacology. 2019 ; Vol. 862.
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    AU - Emami, Arya

    AU - Shojaei, Shahla

    AU - da Silva Rosa, Simone C.

    AU - Aghaei, Mahmoud

    AU - Samiei, Ehsan

    AU - Vosoughi, Amir Reza

    AU - Kalantari, Forouh

    AU - Kawalec, Philip

    AU - Thliveris, James

    AU - Sharma, Pawan

    AU - Zeki, Amir

    AU - Akbari, Mohsen

    AU - Gordon, Joseph W.

    AU - Ghavami, Saeid

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    N2 - 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.

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