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J Clin Med. 2019 May 16;8(5). pii: E694. doi: 10.3390/jcm8050694.

Diverse Action of Selected Statins on Skeletal Muscle Cells-An Attempt to Explain the Protective Effect of Geranylgeraniol (GGOH) in Statin-Associated Myopathy (SAM).

Author information

1
Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences-SGGW, Warsaw, 02-787 Mazowieckie, Poland. ancpatrin@gmail.com.
2
Independent Laboratory of Genetics and Molecular Biology, The General Karol Kaczkowski Military Institute of Hygiene and Epidemiology, Warsaw, 01-163 Mazowieckie, Poland. bepaj@wp.pl.
3
Faculty of Biology and Environmental Protection, University of Łódź, 90-236 Łódzkie, Poland. magdalena.labieniec@biol.uni.lodz.pl.
4
Department of Biomedical and Clinical Sciences "Luigi Sacco", Università degli Studi di Milano, 20157 Milano, Italy. depalma.clara@asst-fbf-sacco.it.
5
Unit of Clinical Pharmacology, University Hospital "Luigi Sacco"-ASST Fatebenefratelli Sacco, 20157 Milano, Italy. depalma.clara@asst-fbf-sacco.it.
6
Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences-SGGW, Warsaw, 02-787 Mazowieckie, Poland. orzechowski_arkadiusz@wp.pl.

Abstract

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

PMID:
31100888
DOI:
10.3390/jcm8050694
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