A systems biology strategy reveals biological pathways and plasma biomarker candidates for potentially toxic statin-induced changes in muscle.
BACKGROUND
Aggressive lipid lowering with high doses of statins increases the risk of statin-induced myopathy. However, the cellular mechanisms leading to muscle damage are not known and sensitive biomarkers are needed to identify patients at risk of developing statin-induced serious side effects.


METHODS
We performed bioinformatics analysis of whole genome expression profiling of muscle specimens and UPLC/MS based lipidomics analyses of plasma samples obtained in an earlier randomized trial from patients either on high dose simvastatin (80 mg), atorvastatin (40 mg), or placebo.


RESULTS
High dose simvastatin treatment resulted in 111 differentially expressed genes (1.5-fold change and p-value<0.05), while expression of only one and five genes was altered in the placebo and atorvastatin groups, respectively. The Gene Set Enrichment Analysis identified several affected pathways (23 gene lists with False Discovery Rate q-value<0.1) in muscle following high dose simvastatin, including eicosanoid synthesis and Phospholipase C pathways. Using lipidomic analysis we identified previously uncharacterized drug-specific changes in the plasma lipid profile despite similar statin-induced changes in plasma LDL-cholesterol. We also found that the plasma lipidomic changes following simvastatin treatment correlate with the muscle expression of the arachidonate 5-lipoxygenase-activating protein.


CONCLUSIONS
High dose simvastatin affects multiple metabolic and signaling pathways in skeletal muscle, including the pro-inflammatory pathways. Thus, our results demonstrate that clinically used high statin dosages may lead to unexpected metabolic effects in non-hepatic tissues. The lipidomic profiles may serve as highly sensitive biomarkers of statin-induced metabolic alterations in muscle and may thus allow us to identify patients who should be treated with a lower dose to prevent a possible toxicity.
Laaksonen
Reijo
R
Research Unit, University Hospital of Tampere, Tampere, Finland. reijo.laaksonen@helsinki.fi
Katajamaa
Mikko
M
Päivä
Hannu
H
Sysi-Aho
Marko
M
Saarinen
Lilli
L
Junni
Päivi
P
Lütjohann
Dieter
D
Smet
Joél
J
Van Coster
Rudy
R
Seppänen-Laakso
Tuulikki
T
Lehtimäki
Terho
T
Soini
Juhani
J
Oresic
Matej
M
D000069059:Atorvastatin; D015415:Biomarkers / Q000097:blood; D019295:Computational Biology; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D008055:Lipids / Q000097:blood; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009135:Muscular Diseases / Q000097:blood* / Q000139:chemically induced* / Q000235:genetics; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects; D019821:Simvastatin / Q000008:administration & dosage / Q000009:adverse effects; D049490:Systems Biology
D015415:Biomarkers; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D011758:Pyrroles; D000069059:Atorvastatin; D019821:Simvastatin