The present study is centered on molecular mechanisms of the cytoprotective effect of geranylgeraniol (GGOH) in skeletal muscle harmed by statin-associated myopathy (SAM). GGOH via autophagy induction was purportedly assumed to prevent skeletal muscle viability impaired by statins, atorvastatin (ATR) or simvastatin (SIM). The C2C12 cell line was used as the 'in vitro' model of muscle cells at different stages of muscle formation, and the effect of ATR or SIM on the cell viability, protein expression and mitochondrial respiration were tested. Autophagy seems to be important for the differentiation of muscle cells; however, it did not participate in the observed GGOH cytoprotective effects. We showed that ATR- and SIM-dependent loss in cell viability was reversed by GGOH co-treatment, although GGOH did not reverse the ATR-induced drop in the cytochrome c oxidase protein expression level. It has been unambiguously revealed that the mitochondria of C2C12 cells are not sensitive to SIM, although ATR effectively inhibits mitochondrial respiration. GGOH restored proper mitochondria functioning. Apoptosis might, to some extent, explain the lower viability of statin-treated myotubes as the pan-caspase inhibitor, N-Benzyloxycarbonyl-Val-Ala-Asp(O-Me) fluoromethyl ketone (Z-VAD-FMK), partly reversed ATR- or SIM-induced cytotoxic effects; however, it does not do so in conjunction with caspase-3. It appears that the calpain inhibitor, N-Acetyl-L-leucyl-L-leucyl-L-norleucinal (ALLM), restored the viability that was reduced by ATR and SIM (p < 0.001). GGOH prevents SAM, in part, as a consequence of a caspase-3 independent pathway, probably by calpain system inactivation.
Keywords: geranylgeraniol; mitochondrial bioenergetics; myotoxicity; skeletal muscle cell viability; statin-associated myopathy; statins; water-soluble cholesterol.
Conflict of interest statement
The authors declare that there is no conflict of interests regarding the publication of this paper.
Geranylgeraniol Prevents Statin-Dependent Myotoxicity in C2C12 Muscle Cells through RAP1 GTPase Prenylation and Cytoprotective Autophagy.Oxid Med Cell Longev. 2018 May 21;2018:6463807. doi: 10.1155/2018/6463807. eCollection 2018. Oxid Med Cell Longev. 2018. PMID: 29951166 Free PMC article.
Geranylgeraniol prevents statin-induced skeletal muscle fatigue without causing adverse effects in cardiac or vascular smooth muscle performance.Transl Res. 2020 Jan;215:17-30. doi: 10.1016/j.trsl.2019.08.004. Epub 2019 Aug 19. Transl Res. 2020. PMID: 31491372
Preliminary Study on Clusterin Protein (sCLU) Expression in PC-12 Cells Overexpressing Wild-Type and Mutated (Swedish) AβPP genes Affected by Non-Steroid Isoprenoids and Water-Soluble Cholesterol.Int J Mol Sci. 2019 Mar 24;20(6):1481. doi: 10.3390/ijms20061481. Int J Mol Sci. 2019. PMID: 30909654 Free PMC article.
Statin-induced Myopathy in Skeletal Muscle: the Role of Exercise.J Lifestyle Med. 2014 Sep;4(2):71-9. doi: 10.15280/jlm.2014.4.2.71. Epub 2014 Sep 30. J Lifestyle Med. 2014. PMID: 26064857 Free PMC article. Review.
The role of mitochondria in statin-induced myopathy.Eur J Clin Invest. 2015 Jul;45(7):745-54. doi: 10.1111/eci.12461. Epub 2015 Jun 15. Eur J Clin Invest. 2015. PMID: 25991405 Review.
Cited by 1 article
Cerivastatin for lowering lipids.Cochrane Database Syst Rev. 2020 Jan 25;1(1):CD012501. doi: 10.1002/14651858.CD012501.pub2. Cochrane Database Syst Rev. 2020. PMID: 31981471 Review.