Muscle Research Unit, Experimental and Clinical Research Center, a joint cooperation between the Charité Universitätsmedizin and the Max Delbrück Center for Molecular Medicine, Berlin, 13125, Germany.
Charité Universitätsmedizin Berlin, Berlin, 13125, Germany.
Sci Rep. 2020 Feb 7;10(1):2158. doi: 10.1038/s41598-020-58668-2.
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.
他汀类药物相关的肌肉副作用是一个持续存在的医疗保健问题，因为患者的依从性取决于副作用。他汀类药物降低血浆胆固醇水平，可预防继发性心血管疾病。尽管已经研究了他汀类药物引起的肌肉损伤，但尚未报道预防或治疗性疗法。我们将原代人肌细胞群体（n = 22）暴露于亲脂性（辛伐他汀）和亲水性（瑞舒伐他汀）他汀类药物中，并分析了它们的表达谱。数据和途径分析包括 GOrilla、Reactome 和 DAVID。我们在细胞内测量了甲羟戊酸，并分析了人肌细胞分泌的类二十烷酸谱。功能测定包括增殖和分化定量。暴露于他汀类药物后，超过 1800 个转录本和 900 个蛋白质的表达水平存在差异。辛伐他汀对表达谱的影响强于瑞舒伐他汀，但两种他汀类药物均影响胆固醇生物合成、脂肪酸代谢、类二十烷酸合成、人肌细胞增殖和分化。培养的人肌细胞分泌 ω-3 和 ω-6 衍生的类二十烷酸和前列腺素。从辛伐他汀处理的原代人肌细胞分泌的 ω-6 衍生代谢物水平更高。类二十烷酸可挽救肌细胞分化。我们的数据提示骨骼肌在胆固醇代谢中具有新的作用。从临床实践的角度来看，添加ω-n 脂肪酸可能适合预防或治疗他汀类药物诱导的肌病。
