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Molecular mechanisms of statin-associated myotoxicity

Bonifacio, Annalisa. Molecular mechanisms of statin-associated myotoxicity. 2014, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_11696

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Abstract

Statins, hydroxyl-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are cholesterol-lowering drugs that are majorly used to treat hypercholesterolaemia and dyslipidaemia implicated in the pathogenesis of coronary heart disease and atherosclerosis [1]. They are generally considered safe drugs, but there are a number of reports of skeletal muscle damage associated with their use [2]. The myotoxicity ranges from a mild clinical syndrome consisting of benign myalgia to rare but life-threating rhabdomyolysis [3]. These side-effects can impact on quality of life and compliance, and in extreme cases lead to death [4]. Because millions of people in the world are currently taking statins every day, it is an urgent task to uncover the mechanism by which statins lead to side effects [5].
This thesis includes two published papers and one still in preparation.
Our first paper presents a comparison between three different statins on the market: simvastatin, atorvastatin and rosuvastatin. Since there are differences among statins in terms of their efficacy and toxicity, we aimed to analyze the different molecular mechanisms that may contribute to the diverse grade of toxicity between simvastatin, atorvastatin and rosuvastatin. Simvastatin and atorvastatin appear to have a higher than average risk of myotoxicity contributing to the highest number of cases of rhabdomyolysis among statins [6] [7]. On the contrary rosuvastatin, the most hydrophilic statin, appears to have a reduced myotoxicity [8] [7]. C2C12 myotubes were exposed to 10 µM or 50 µM simvastatin, rosuvastatin or atorvastatin for 24 hours. We demonstrated that myotubes were more susceptible to simvastatin and atorvastatin than to rosuvastatin treatment. Therefore, difference between rosuvastatin and atorvastatin or simvastatin could point to possible mechanisms of toxicity. The cytotoxicity of simvastatin and atorvastatin was associated with a drastic and dose-dependent impairment of AKT signaling cascade that led to inhibition of the protein synthesis, increase of the protein degradation and promotion of apoptosis. Conversely, rosuvastatin blocked AKT signaling only at high concentration and to a lesser extent compared with the other two statins. The reduced effect on cytotoxicity and AKT signaling inhibition in C2C12 myotubes treated with rosuvastatin was accompanied with normal protein synthesis and absence of protein degradation and apoptosis. These results provide evidence that an impairment of AKT signaling pathways might be a causative factor in statin-induced myotoxicity.
Our second paper expands on these previous results by showing that the myotoxicity, and with it, the impairment of AKT signaling, can be prevented by the addition of IGF-1. IGF-1 is well known for exerting an anabolic effect on skeletal muscle [9] by activating IGF-1/AKT pathway [10]. Therefore we investigated whether IGF-1 could antagonize the myotoxicity induced by statins. Myotubes were exposed to 10 µM simvastatin and/or 20 ng/ml IGF-1 for 18 hours. Simvastatin-induced myotoxicity was completely antagonized by IGF-1. Moreover, the protective effect of IGF-1 was mediated by the activation of IGF-1/AKT pathway that led to a suppression of atrophic markers and apoptosis, and simultaneously triggered pro-synthetic pathways. These studies provide new insight into the prevention of statin toxicity and may herald new discoveries for the treatment of statin-induced myalgia.
The final paper takes the work of the previous two papers and places it into a novel system: the cardiac muscle. Statins are primarily prescribed to cure and prevent cardiovascular disease. Thus, cardiac side-effects may be masked by falsely attributing them to the underlying disease. In this paper, we investigated on the effect of simvastatin in cardiomyocyte in vitro and in vivo. We treated H9c2 rat cardiomyocytes with 10 µM and 100 µM simvastatin for 24 hours. H9c2 cells showed a reduction in the mitochondrial membrane potential and energetic impairment linked to mitochondrial dysfunction. Consequently, the cellular ATP level was decreased. This decrease led to the activation of AMPK, nuclear translocation of FoxO3, upregulation of atrogin-1 and initiation of apoptosis. We confirmed these results in vivo. We demonstrated that the treatment of mice with simvastatin 5 mg/kg/day for 21 days impaired the activity of several enzyme complexes of the electron transport chain in cardiomyocytes and increased mRNA expression of atrogin-1 and markers of apoptosis. This is the first study that shows energetic impairment linked to atrophy and apoptosis induced by statins in the heart, and warrants further investigation to assess statin safety in susceptible patients.
Advisors:Krähenbühl, Stephan and Arand, Michael
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie > Klinische Pharmakologie (Krähenbühl)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie > Klinische Pharmakologie (Krähenbühl)
Item Type:Thesis
Thesis no:11696
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (IV, 94 Seiten)
Language:English
Identification Number:
Last Modified:29 Aug 2016 09:29
Deposited On:29 Aug 2016 09:29

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