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Statin-induced skeletal muscle toxicity: role of statin transport into myocytes and of the IGF-1R signalling pathway
| Third-party funded project |
| Project title |
Statin-induced skeletal muscle toxicity: role of statin transport into myocytes and of the IGF-1R signalling pathway |
| Principal Investigator(s) |
Krähenbühl, Stephan
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| Organisation / Research unit |
Departement Biomedizin / Clinical Pharmacology (Krähenbühl) |
| Project start |
01.10.2010 |
| Probable end |
30.09.2013 |
| Status |
Completed |
| Abstract |
Statins, hydroxyl-methyl-glutaryl-coenzyme A reductase inhibitors, are among the most prescribed drugs in Western countries. They reduce morbidity and mortality in patients with cardiovascular disease and are generally well tolerated. However, myopathy is the major side effect occurring in approximately 0.1% of patients who receive statin monotherapy. The mechanisms of statin-induced myopathy are not fully elucidated.
In the first project (Stephan Krähenbühl) we propose to investigate the mechanisms leading to increased expression of atrogin-1 in patients treated with statins. Atrogin-1 has been reported as a central factor driving muscle atrophy and recent work suggests a role of atrogin-1 also in statin induced myopathy. Two observations are important to understand the rational of our projects: 1. Igf-1R signalling has been shown to affect atrogin-1 expression and 2. Atrogin-1 expression can be decreased in vitro by the cholesterol precursors GGOH or mevalonate. So far, however, the precise mechanism of how statins interfere with Igf-1R signalling and induction of atrogin-1 in muscle cells is unclear. We therefore propose the following projects. First, we will investigate whether inhibition of the mevalonate pathway by statins leading to a decrease in dolichol intermediates results in a decline in N-linked glycosylation of Igf-1R, thereby impairing signal transduction of Igf-1. Second, we will study the impact of insulin on Igf-1R signalling. The protective effect of insulin in statin treated myotubes has never been investigated so far. Third, we will explore the function of geranylated small GTPases in Igf-1R signalling.
In the second project (Bruno Stieger) the role of active transport into skeletal muscle cells for statin-associated myotoxicity will be investigated. Several studies in patients and in cultured cells have shown the importance of organic anion transporters for the effect and also adverse reactions of statins. The proposed project aims to further establish the importance of these transporters for the cellular uptake, and, related to that, for cytotoxicity of statins. First, the transport of statins will be studied using CHO cells overexpressing specific OATPs. Using this information, transport and related cytotoxicity will be studied in human (RD cells), rat (L6 cells) and mouse (C2C12 cells) cell lines. After overexpression of OATP1B1 (a carrier whose importance in the transport of simvastatin has been well characterized) cytotoxicity can be compared to OATP1B1 overexpressing and wild type cells. Using a proteomic approach, mechanisms of cytotoxicity will further be investigated depending on the activity of cellular transport systems.
The proposed projects aim both at providing mechanisms for the clinically important statin-associated myopathies. They both have the potential to provide drug targets for the prevention of statin-associated myotoxicity and candidate genes for predicting patients at risk. |
| Financed by |
Swiss National Science Foundation (SNSF)
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02/05/2024
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