Statins reduce plasma cholesterol levels and are effective in secondary cardiovascular disease prevention. However, statin related muscle side effects are a constant problem for patients and doctors because compliance in taking them is severely influenced by the side effects. The mechanism of statin-myopathy remains unknown.We exposed primary human muscle cell lines (n=4) to a lipophilic (simvastatin) and a hydrophilic More than 1800 transcripts and 900 proteins were differentially expressed after exposure to statins.Simvastatin had a much worse effect on the expressome than rosuvastatin, but both statins had a severe impact on cholesterol biosynthesis, fatty acid metabolism, eicosanoid synthesis, proliferation, and differentiation of human muscle cells. Eicosanoids rescued the biological function. We also found that muscle cells were very similarly equipped for cholesterol biosynthesis than HepG2 cell.Our data bring a new aspect to the role of skeletal muscle in cholesterol metabolism. For clinical practice, the addition of omega-3,6 fatty acids could be suitable to prevent or treat statin-myopathy.