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 language | English (US) |
|---|---|
| Article number | 172616 |
| Journal | European Journal of Pharmacology |
| Volume | 862 |
| DOIs | |
| State | Published - Nov 5 2019 |
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Keywords
- 3D culture model
- Autophagy flux
- Prenylation
- Rhabdomyosarcoma
- Statin
ASJC Scopus subject areas
- Pharmacology
Cite this
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 journal › Article
}
TY - JOUR
T1 - Mechanisms of simvastatin myotoxicity
T2 - The role of autophagy flux inhibition
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
PY - 2019/11/5
Y1 - 2019/11/5
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.
AB - 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.
KW - 3D culture model
KW - Autophagy flux
KW - Prenylation
KW - Rhabdomyosarcoma
KW - Statin
UR - http://www.scopus.com/inward/record.url?scp=85071732867&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071732867&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2019.172616
DO - 10.1016/j.ejphar.2019.172616
M3 - Article
C2 - 31449810
AN - SCOPUS:85071732867
VL - 862
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
M1 - 172616
ER -