The glucocorticoid-induced leucine zipper mediates statin-induced muscle damage

Jessica Hoppstädter, Jenny Vanessa Valbuena Perez, Rebecca Linnenberger, Charlotte Dahlem, Thierry M. Legroux, Anne Hecksteden, William K.F. Tse, Sara Flamini, Anastasia Andreas, Jennifer Herrmann, Christian Herr, Rolf Müller, Tim Meyer, Robert Bals, Carlo Riccardi, Stefano Bruscoli, Alexandra K. Kiemer

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Statins, the most prescribed class of drugs for the treatment of hypercholesterolemia, can cause muscle-related adverse effects. It has been shown that the glucocorticoid-induced leucine zipper (GILZ) plays a key role in the anti-myogenic action of dexamethasone. In the present study, we aimed to evaluate the role of GILZ in statin-induced myopathy. Statins induced GILZ expression in C2C12 cells, primary murine myoblasts/myotubes, primary human myoblasts, and in vivo in zebrafish embryos and human quadriceps femoris muscle. Gilz induction was mediated by FOXO3 activation and binding to the Gilz promoter, and could be reversed by the addition of geranylgeranyl, but not farnesyl, pyrophosphate. Atorvastatin decreased Akt phosphorylation and increased cleaved caspase-3 levels in myoblasts. This effect was reversed in myoblasts from GILZ knockout mice. Similarly, myofibers isolated from knockout animals were more resistant toward statin-induced cell death than their wild-type counterparts. Statins also impaired myoblast differentiation, and this effect was accompanied by GILZ induction. The in vivo relevance of our findings was supported by the observation that gilz overexpression in zebrafish embryos led to impaired embryonic muscle development. Taken together, our data point toward GILZ as an essential mediator of the molecular mechanisms leading to statin-induced muscle damage.

Original languageEnglish
Pages (from-to)4684-4701
Number of pages18
JournalFASEB Journal
Volume34
Issue number3
DOIs
Publication statusPublished - Mar 1 2020

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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