Statins promote muscle metabolic danger and NLRP3-mediated myopathy via lower protein-prenylation and YAP
Abstract
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 statinmediated 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.
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BibTeX
@article{robin2026statins,
title = {{Statins promote muscle metabolic danger and NLRP3-mediated myopathy via lower protein-prenylation and YAP}},
author = {Nazli Robin and Nicole Barra and Kevin Foley and Yujin Li and Akhilesh Tamrakar and Danish Patoli and Irena Rebalka and Tabitha Cree and Kaitlyn Bibby and Khang Nguyen and Rhianna Davis and Darryl Chan and Brittany Duggan and Brandyn Henriksbo and Megan Borges and Dana Kukje Zada and Han Fang and Daniel Marko and Paul Gregorevic and Kevin Watt and Richard Mills and Gary Sweeney and Thomas Hawke and Bénédicte Py and Jonathan Schertzer},
journal = {Science Advances},
year = {2026},
month = jun,
doi = {10.1126/sciadv.adz3612},
url = {https://hal.science/hal-05772298v1},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Statins promote muscle metabolic danger and NLRP3-mediated myopathy via lower protein-prenylation and YAP
AU - Nazli Robin
AU - Nicole Barra
AU - Kevin Foley
AU - Yujin Li
AU - Akhilesh Tamrakar
AU - Danish Patoli
AU - Irena Rebalka
AU - Tabitha Cree
AU - Kaitlyn Bibby
AU - Khang Nguyen
AU - Rhianna Davis
AU - Darryl Chan
AU - Brittany Duggan
AU - Brandyn Henriksbo
AU - Megan Borges
AU - Dana Kukje Zada
AU - Han Fang
AU - Daniel Marko
AU - Paul Gregorevic
AU - Kevin Watt
AU - Richard Mills
AU - Gary Sweeney
AU - Thomas Hawke
AU - Bénédicte Py
AU - Jonathan Schertzer
PY - 2026
DA - 2026/06/19
JO - Science Advances
DO - 10.1126/sciadv.adz3612
UR - https://hal.science/hal-05772298v1
AB - 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 statinmediated 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.
SN - 2375-2548
ER -