A Systems Biology Strategy Reveals Biological Pathways and Plasma Biomarker Candidates for Potentially Toxic Statin-Induced Changes in Muscle

Abstract

BackgroundAggressive 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.MethodologyWe 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 FindingsHigh 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.ConclusionsHigh 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.

Statin or fibrate chronic treatment modifies the proteomic profile of rat skeletal muscle

“…S1). In parallel, other studies performed by using combined genomic and lipidomic analysis showed changes in muscle metabolism (dysregulation of calcium binding proteins and phospholipase C pathway, defective mitochondrial metabolism and activation of pro-apoptosis pathway, dysregulation of cell membrane lipids) contributing to muscle toxicity [39]. Our results showed a down-regulation of several muscle proteins and this effect was…”

“…This latter finding can be a consequence of the inhibition of the specific targets of the two drugs. Otherwise, the prevalent effect of atorvastatin on the oxidative metabolism pathway can be related to the already described statin-mediated mitochondrial involvement [17,19,39]. Yet, since fenofibrate have no effects on calcium released by mitochondria [17], likely slight effect on the oxidative metabolism were observed here.…”

“…An effect of statin on HSPs expression has been previously observed in other tissues, such as human placental cells line [57] and rat retina during ischemia [58]. Together with the decrease of muscle plasmalogens, a sub-class of ether phospholipids involved in protection against oxidative damage [39], these effects suggest an accentuated sensitivity of statin-treated muscles to oxidative stress. Oxidative stress has been pinpointed as a likely trigger of many conditions of muscle wasting [59][60].…”

Metabolomic changes in fatty liver can be modified by dietary protein and calcium during energy restriction

“…The compounds were detected by using electrospray ionization in positive ion mode (ESI+). Data was collected at m/z 300-1200 with a scan duration of 0.2 s. Data was processed using MZmine software version 0.60 [27,28] , and metabolites were identified using internal spectral library or with tandem mass spectrometry as previously described [6,29] .…”

Hepatic Stearoyl-CoA Desaturase (SCD)-1 Activity and Diacylglycerol but Not Ceramide Concentrations Are Increased in the Nonalcoholic Human Fatty Liver

“…Sphingomyelins and diacylglycerols were calibrated with PC (17:0/17:0) as an internal standard, while all lysophospholipids were normalized using lysoPC (17:0). Characteristics of the analytical method have been described in detail in the supplement of our previous study (26). The applied platform affords broad screening of multiple lipid classes, including triacylglycerols, cholesterol esters, and major phospholipids, from total lipid extracts within a single sample run.…”