The glucocorticoid-induced leucine zipper mediates statin-induced muscle damage.
Animals
Blotting, Western
Cell Line
Cells, Cultured
Chromatin Immunoprecipitation
Fluorescent Antibody Technique
Glucocorticoids
/ pharmacology
Humans
In Situ Hybridization
Lentivirus
/ genetics
Leucine Zippers
/ physiology
Mice
Mice, Inbred C57BL
Muscles
/ drug effects
Polyisoprenyl Phosphates
/ pharmacology
Zebrafish
Tsc22d3
flexor digitorum brevis
HMG-CoA
muscle wasting
statin-associated muscle symptoms
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
08
10
2019
revised:
21
01
2020
accepted:
21
01
2020
pubmed:
8
2
2020
medline:
22
1
2021
entrez:
8
2
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32030813
doi: 10.1096/fj.201902557RRR
doi:
Substances chimiques
Glucocorticoids
0
Polyisoprenyl Phosphates
0
geranylgeranyl pyrophosphate
N21T0D88LX
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4684-4701Informations de copyright
© 2020 The Authors. The FASEB Journal published by Wiley Periodicals, Inc. on behalf of Federation of American Societies for Experimental Biology.
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