The role of caveolae in statin-induced myopathy

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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.