Abstract
Statin-related muscle side effects are a constant healthcare problem since patient compliance is dependent on side effects. Statins reduce plasma cholesterol levels and can prevent secondary cardiovascular diseases. Although statin-induced muscle damage has been studied, preventive or curative therapies are yet to be reported. We exposed primary human muscle cell populations (n = 22) to a lipophilic (simvastatin) and a hydrophilic (rosuvastatin) statin and analyzed their expressome. Data and pathway analyses included GOrilla, Reactome and DAVID. We measured mevalonate intracellularly and analyzed eicosanoid profiles secreted by human muscle cells. Functional assays included proliferation and differentiation quantification. More than 1800 transcripts and 900 proteins were differentially expressed after exposure to statins. Simvastatin had a stronger effect on the expressome than rosuvastatin, but both statins influenced cholesterol biosynthesis, fatty acid metabolism, eicosanoid synthesis, proliferation, and differentiation of human muscle cells. Cultured human muscle cells secreted ω-3 and ω-6 derived eicosanoids and prostaglandins. The ω-6 derived metabolites were found at higher levels secreted from simvastatin-treated primary human muscle cells. Eicosanoids rescued muscle cell differentiation. Our data suggest a new aspect on the role of skeletal muscle in cholesterol metabolism. For clinical practice, the addition of omega-n fatty acids might be suitable to prevent or treat statin-myopathy.
Highlights
Statin-related muscle side effects are a constant healthcare problem since patient compliance is dependent on side effects
In primary human muscle cell populations obtained from 22 patients we investigated key signalling pathways that are significantly interfered by statins in muscle cells and their impact on cellular and molecular levels
We found that simvastatin had a dramatic effect on primary human muscle cells, much more than rosuvastatin. 1807 genes (FDR < 0.05) were differentially expressed after exposure to simvastatin (Fig. 1B, Supplementary Table S2, Supplementary Dataset File 1)
Summary
Statin-related muscle side effects are a constant healthcare problem since patient compliance is dependent on side effects. Simvastatin had a stronger effect on the expressome than rosuvastatin, but both statins influenced cholesterol biosynthesis, fatty acid metabolism, eicosanoid synthesis, proliferation, and differentiation of human muscle cells. The ω-6 derived metabolites were found at higher levels secreted from simvastatin-treated primary human muscle cells. Hypotheses for statin-related side effects include a decrease in ubiquinone synthesis, cholesterol, and vitamin D levels, and a loss of isoprenoid metabolites. We chose an integrated approach to study the effects of a lipophilic and a hydrophilic statin in many individual primary human myoblast cells at molecular, cellular, and functional levels[21]. Our model for signal transduction pathway suggests statin-induced metabolic changes upstream of mevalonate, in mitochondrial ß-oxidation and eicosanoid synthesis. Eicosanoid-species substitution to simvastatin-treated primary human muscle cells rescue these effects. Appears as a distinct and potentially treatable myopathy driven by HMG-CoA accumulation rather than mevalonate depletion
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