Statins promote muscle metabolic danger and NLRP3-mediated myopathy via lower protein-prenylation and YAP.

Statin intolerance and side effects such as low-level myopathy limit statin use and the dose for optimal cholesterol lowering. We found that priming the NLRP3 inflammasome with bacterial components like lipopolysaccharide lowered the dose of statins that caused side effects in muscle cells. We then built models of low-level statin myopathy and found that muscle cell-autonomous statin-induced myopathy occurs through the NLRP3 inflammasome in vitro and in mice. Statin-induced muscle cell death and higher Atrogin-1 were prevented by blocking NLRP3 or restoring isoprenoids but not cholesterol. Statins reduced glycolysis in muscle cells, which required lower protein prenylation. Statins lowered YAP effector genes and promoted nuclear accumulation of FOXO. Activating YAP, restoring isoprenoids, or blocking NLRP3 mitigated nuclear FOXO accumulation, statin-induced muscle atrophy, and statin-mediated lowering of protein synthesis. These results define a statin-induced myopathy pathway where metabolic danger engages the NLRP3 inflammasome and YAP via lower prenylation independent of cholesterol.