Statins activate the NLRP3 inflammasome and inhibit the Hippo pathway to promote myopathy

High blood cholesterol affects ~30% of adult Canadians and doubles the risk of cardiac events. Statins are widely used for lowering cholesterol levels, but statins have pleiotropic effects that can be mediated by lowering protein prenylation. The most prevalent side effect of statin therapy is myopathy. Overt myotoxicity and rhabdomyolysis are rare (S127A) in C2C12 mitigated statin-mediated increases in atrogin-1 and lower myotube diameter compared to vector/vehicle controls in LPS primed myotubes. Statins also promoted the nuclear accumulation of FOXO1 and decreased levels of phosphorylated FOXO1/3a. Restoring protein prenylation and blocking the NLRP3 inflammasome prevented statin-induced nuclear accumulation of FOXO1 and mitigated decreased levels of p-FOXO1/3a. These results showed that prenylation and activation of NLRP3 inflammasome are both upstream of the FOXO activation. Our results demonstrated that activation of YAP in the presence of statins mitigated measures of statin-induced myopathy and that NLRP3 activation is upstream of FOXO activation, which is a known regulator of Atrogin-1. Further investigation to characterize the mechanism of statin-induced myopathy can lead to an enhanced understanding of statin-induced myopathy and the establishment of next-generation statin therapies without muscular side effects. Natural Sciences and Engineering Research Council (NSERC) of Canada This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.