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Molecular mechanisms of statin-induced myotoxicity

Mullen, Peter James. Molecular mechanisms of statin-induced myotoxicity. 2011, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_9421

Abstract

Statins are among the most prescribed drugs in Western countries. They reduce morbidity and mortality from coronary heart disease and mitigate the risk of stroke. Their major site of action is the liver, where they inhibit HMG-CoA (hydroxyl-methyl-glutaryl-coenzyme A) reductase, the rate-limiting step in cholesterol biosynthesis. Inhibition of this pathway also inhibits various other processes, such as ubiquinone production and the isoprenylation and N-linked glycosylation of proteins. Altering these processes can reduce inflammation, oxidative stress and platelet adhesion ñ leading to the positive effects of statins. However, inhibition of these processes can also lead to negative side-effects, such as skeletal muscle myopathy, which is seen in 1ñ5% of patients. These side-effects can impact on quality of life and compliance, and in extreme cases lead to death. Uncovering the mechanism by which statins lead to these side-effects is therefore of great urgency.
This thesis includes three papers that have been published or submitted for publication.
Our first paper presents a comprehensive comparison of the effects of simvastatin on the cholesterol pathway and its intermediates in mouse skeletal muscle C2C12 myotubes and human liver HepG2 cells. C2C12 myotubes are susceptible to statin-induced toxicity, whereas HepG2 cells are not. Differences between the two could therefore point to possible toxic or protective mechanisms. We show that differences in ubiquinone and cholesterol content are not responsible for toxicity, and suggest that altered geranylgeranylation could cause toxicity in the C2C12 myotubes. We also show a decrease in the rate of N-linked glycosylation in the C2C12 myotubes. This, and the need for geranylgeranylated proteins, suggests that an impairment in cell signalling pathways is responsible for statin-induced toxicity.
Our second paper expands on these results by showing that an impairment in Igf-1/Akt signalling leads to both mitochondrial toxicity and upregulation of the pro-atrophy atrogin-1. We show that Igf-1/Akt signalling is not impaired in the HepG2 cells, and that inhibition of this pathway makes the HepG2 cells sensitive to simvastatin. Finally, we provide evidence that a small GTPase, Rap1, is integral to C2C12 myotube mitochondrial integrity, and that mitochondrial respiration can be partially rescued by expressing constitutively active Rap1 in those cells. Rap1 is a geranylgeranylated protein that has been hypothesized to link cAMP/EPAC signalling to Igf-1/Akt signalling, and is therefore a prime candidate as a causative factor in statin-induced myotoxicity.
The final paper takes the work of the previous two papers and places it into a novel environment ñ cardiac muscle. Statins are primarily prescribed to prevent cardiovascular disease, and we present evidence that suggest that simvastatin can be toxic in cardiomyocytes. We start with an observation of a lighter heart in simvastatin-treated Wistar rats, and use ex vivo cardiomyocytes and in vitro H9C2 cardiomyocytes to confirm toxicity. We show that, similar to the C2C12 myotubes, simvastatin leads to mitochondrial dysfunction, inhibition of Igf-1/Akt signalling and upregulation of atrogin-1 expression. This is the first time that these effects have been seen in the heart, and warrant further investigation to ensure that these effects so not pose a risk in susceptible patients.
Advisors:Krähenbühl, Stephan
Committee Members:Huwyler, Jörg
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmakologie (Krähenbühl)
Item Type:Thesis
Thesis no:9421
Bibsysno:Link to catalogue
Number of Pages:87 Bl.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:42
Deposited On:22 Jun 2011 12:07

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