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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.

The association between SCARB1 rs74830677 (c.1127 C > T, [P.pro 367 leu] P367L) gene polymorphisms and insulin resistance (IR) has been not been analysed and studied. The clinical relevance of these findings remained uncertain and brings into question the importance of SCARB1 in human physiology. So, we investigated the hypothesis the SCARB1 SNPs in association with the risk of developing insulin resistance. A total of 600 individuals, including 300 T2DM and 300 healthy individuals, were enrolled in the study. Blood samples were collected from each T2DM and healthy individual. CT method for the relative quantitation were used for gene expression level in T2DM and healthy controls. Also, restriction fragment length polymorphism analysis was achieved to detect the incidence of genetic polymorphisms. HOMA resistance index and QUICKI were calculated from fasting plasma glucose and insulin values. In the present study, there was strong association observed between T2DM and SCARB1 rs74830677 gene polymorphism (OR = 1.7, 95% CI 1.18–2.71, P = 0.07). Further, T allele were associated with increase serum insulin and HOMA-IR. Our genotyping data showed that SCARB1 rs7480677 variant is significantly higher in subjects with increased HOMA-IR. Thus, we conclude that SCARB1 polymorphisms may play a crucial role in pathogenesis and susceptibility of insulin resistance thus leads to the development of type 2 diabetes mellitus.