A systems biology strategy reveals biological pathways and plasma biomarker candidates for potentially toxic statin-induced changes in muscle

R. Laaksonen (Corresponding Author), Mikko Katajamaa, H. Päivä, Marko Sysi-Aho, L. Saarinen, P. Junni, D. Lütjohann, J. Smet, R. Van Coster, Tuulikki Seppänen-Laakso, T. Lehtimäki, J. Soini, Matej Oresic (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

179 Citations (Scopus)

Abstract

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. Methodology: 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. Principal Findings: 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.
Original languageEnglish
Number of pages9
JournalPLoS ONE
Volume1
Issue number1
DOIs
Publication statusPublished - 2006
MoE publication typeA1 Journal article-refereed

Fingerprint

Hydroxymethylglutaryl-CoA Reductase Inhibitors
Systems Biology
Poisons
Biomarkers
Simvastatin
Muscle
biomarkers
Plasmas
Genes
Biological Sciences
Muscles
muscles
dosage
5-Lipoxygenase-Activating Proteins
placebos
Placebos
genes
Lipids
Eicosanoids
Type C Phospholipases

Cite this

Laaksonen, R. ; Katajamaa, Mikko ; Päivä, H. ; Sysi-Aho, Marko ; Saarinen, L. ; Junni, P. ; Lütjohann, D. ; Smet, J. ; Van Coster, R. ; Seppänen-Laakso, Tuulikki ; Lehtimäki, T. ; Soini, J. ; Oresic, Matej. / A systems biology strategy reveals biological pathways and plasma biomarker candidates for potentially toxic statin-induced changes in muscle. In: PLoS ONE. 2006 ; Vol. 1, No. 1.
@article{0e1cfd5f3e9c4f27bff48e36886e612c,
title = "A systems biology strategy reveals biological pathways and plasma biomarker candidates for potentially toxic statin-induced changes in muscle",
abstract = "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. Methodology: 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. Principal Findings: 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.",
author = "R. Laaksonen and Mikko Katajamaa and H. P{\"a}iv{\"a} and Marko Sysi-Aho and L. Saarinen and P. Junni and D. L{\"u}tjohann and J. Smet and {Van Coster}, R. and Tuulikki Sepp{\"a}nen-Laakso and T. Lehtim{\"a}ki and J. Soini and Matej Oresic",
year = "2006",
doi = "10.1371/journal.pone.0000097",
language = "English",
volume = "1",
journal = "PLoS ONE",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "1",

}

Laaksonen, R, Katajamaa, M, Päivä, H, Sysi-Aho, M, Saarinen, L, Junni, P, Lütjohann, D, Smet, J, Van Coster, R, Seppänen-Laakso, T, Lehtimäki, T, Soini, J & Oresic, M 2006, 'A systems biology strategy reveals biological pathways and plasma biomarker candidates for potentially toxic statin-induced changes in muscle', PLoS ONE, vol. 1, no. 1. https://doi.org/10.1371/journal.pone.0000097

A systems biology strategy reveals biological pathways and plasma biomarker candidates for potentially toxic statin-induced changes in muscle. / Laaksonen, R. (Corresponding Author); Katajamaa, Mikko; Päivä, H.; Sysi-Aho, Marko; Saarinen, L.; Junni, P.; Lütjohann, D.; Smet, J.; Van Coster, R.; Seppänen-Laakso, Tuulikki; Lehtimäki, T.; Soini, J.; Oresic, Matej (Corresponding Author).

In: PLoS ONE, Vol. 1, No. 1, 2006.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - A systems biology strategy reveals biological pathways and plasma biomarker candidates for potentially toxic statin-induced changes in muscle

AU - Laaksonen, R.

AU - Katajamaa, Mikko

AU - Päivä, H.

AU - Sysi-Aho, Marko

AU - Saarinen, L.

AU - Junni, P.

AU - Lütjohann, D.

AU - Smet, J.

AU - Van Coster, R.

AU - Seppänen-Laakso, Tuulikki

AU - Lehtimäki, T.

AU - Soini, J.

AU - Oresic, Matej

PY - 2006

Y1 - 2006

N2 - 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. Methodology: 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. Principal Findings: 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.

AB - 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. Methodology: 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. Principal Findings: 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.

U2 - 10.1371/journal.pone.0000097

DO - 10.1371/journal.pone.0000097

M3 - Article

VL - 1

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 1

ER -