Tags

Type your tag names separated by a space and hit enter

A systems biology strategy reveals biological pathways and plasma biomarker candidates for potentially toxic statin-induced changes in muscle.
PLoS One. 2006 Dec 20; 1:e97.Plos

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.

Authors+Show Affiliations

Research Unit, University Hospital of Tampere, Tampere, Finland. reijo.laaksonen@helsinki.fiNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17183729

Citation

Laaksonen, Reijo, et al. "A Systems Biology Strategy Reveals Biological Pathways and Plasma Biomarker Candidates for Potentially Toxic Statin-induced Changes in Muscle." PloS One, vol. 1, 2006, pp. e97.
Laaksonen R, Katajamaa M, Päivä H, et al. A systems biology strategy reveals biological pathways and plasma biomarker candidates for potentially toxic statin-induced changes in muscle. PLoS ONE. 2006;1:e97.
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, 1, e97.
Laaksonen R, et al. A Systems Biology Strategy Reveals Biological Pathways and Plasma Biomarker Candidates for Potentially Toxic Statin-induced Changes in Muscle. PLoS ONE. 2006 Dec 20;1:e97. PubMed PMID: 17183729.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A systems biology strategy reveals biological pathways and plasma biomarker candidates for potentially toxic statin-induced changes in muscle. AU - Laaksonen,Reijo, AU - Katajamaa,Mikko, AU - Päivä,Hannu, AU - Sysi-Aho,Marko, AU - Saarinen,Lilli, AU - Junni,Päivi, AU - Lütjohann,Dieter, AU - Smet,Joél, AU - Van Coster,Rudy, AU - Seppänen-Laakso,Tuulikki, AU - Lehtimäki,Terho, AU - Soini,Juhani, AU - Oresic,Matej, Y1 - 2006/12/20/ PY - 2006/09/08/received PY - 2006/11/21/accepted PY - 2006/12/22/pubmed PY - 2006/12/22/medline PY - 2006/12/22/entrez SP - e97 EP - e97 JF - PloS one JO - PLoS ONE VL - 1 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/17183729/A_systems_biology_strategy_reveals_biological_pathways_and_plasma_biomarker_candidates_for_potentially_toxic_statin_induced_changes_in_muscle_ L2 - http://dx.plos.org/10.1371/journal.pone.0000097 DB - PRIME DP - Unbound Medicine ER -