The role of caveolae in statin-induced myopathy

他汀类药物诱导的肌病的遗传原因，如与肝阴离子转运蛋白基因SLCO 1B 1中的SNP相关，是已知的。然而，这种关联可以解释他汀类药物血浆水平的差异，但不能解释为什么骨骼肌是不良反应的靶点。我们推测他汀类药物引起的肌病起源于骨骼肌。我们在400名服用他汀类药物的个体中进行了与肌痛相关肌病相关的四个候选基因的遗传变异之间的关联研究，发现他汀类肌病与男性caveolin-3基因内的变异之间存在显著关联。小窝蛋白是小窝的主要成分，小窝是质膜上富含胆固醇的内陷。胆固醇消耗导致细胞膜小窝结构的丧失和细胞代谢的深刻改变。此外，通过与雌激素受体的关联，小窝以性别特异性的方式表现出其部分功能。我们将阐明的作用，小窝他汀类药物诱导的肌病相结合的遗传，形态学和功能的方法。该项目可能对他汀类肌病的理解，治疗和预防产生重大影响。

Genetic causes for statin-induced myopathy, such as association with a SNP in hepatic anion transporter gene SLCO1B1, are known. However, this association could account for differences in statin-plasma levels but cannot explain why skeletal muscle is the target of adverse effects. We hypothesize that statin-induced myopathy originates in skeletal muscle. We conducted an association study between genetic variants in four candidate genes related to myalgia-associated myopathies in 400 individuals ingesting statins and found a significant association between statin myopathy and a variant within the caveolin-3 gene, in men. Caveolins are a major component of caveolae, which are cholesterol rich invaginations on the plasma membrane. Cholesterol depletion leads to loss of caveolar structure and profound alterations in cell metabolism. Further, through association with the estrogen receptor, caveolae exhibit part of their function in a gender-specific manner. We will elucidate the role of caveolae in statin-induced myopathy by a combined genetic, morphological, and functional approach. The project could have great impact on the understanding of statin myopathy, its treatment and prevention.