PUBLICATION
Statin-induced muscle damage and atrogin-1 induction is the result of a geranylgeranylation defect
- Authors
- Cao, P., Hanai, J.I., Tanksale, P., Imamura, S., Sukhatme, V.P., and Lecker, S.H.
- ID
- ZDB-PUB-090505-12
- Date
- 2009
- Source
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23(9): 2844-2854 (Journal)
- Registered Authors
- Sukhatme, Vikas
- Keywords
- none
- MeSH Terms
-
- Animals
- Cells, Cultured
- F-Box Proteins/genetics*
- GTP-Binding Proteins
- Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects*
- Lovastatin/adverse effects
- Mice
- Muscle Fibers, Skeletal/drug effects
- Muscle Fibers, Skeletal/pathology*
- Muscle Proteins/genetics*
- Muscular Atrophy/chemically induced*
- Muscular Atrophy/etiology
- Prenylation/genetics*
- SKP Cullin F-Box Protein Ligases/genetics*
- Transcriptional Activation
- Zebrafish
- Zebrafish Proteins/genetics*
- PubMed
- 19406843 Full text @ FASEB J.
- CTD
- 19406843
Citation
Cao, P., Hanai, J.I., Tanksale, P., Imamura, S., Sukhatme, V.P., and Lecker, S.H. (2009) Statin-induced muscle damage and atrogin-1 induction is the result of a geranylgeranylation defect. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 23(9):2844-2854.
Abstract
Statins are widely used to treat hypercholesterolemia but can lead to a number of side effects in muscle, including rhabdomyolysis. Our recent findings implicated the induction of atrogin-1, a gene required for the development of muscle atrophy, in statin-induced muscle damage. Since statins inhibit many biochemical reactions besides cholesterol synthesis, we sought to define the statin-inhibited pathways responsible for atrogin-1 expression and muscle damage. We report here that lovastatin-induced atrogin-1 expression and muscle damage in cultured mouse myotubes and zebrafish can be prevented in the presence of geranylgeranol but not farnesol. Further, inhibitors of the transfer of geranylgeranyl isoprene units to protein targets cause statin muscle damage and atrogin-1 induction in cultured cells and in fish. These findings support the concept that dysfunction of small GTP-binding proteins lead to statin-induced muscle damage since these molecules require modification by geranylgeranyl moieties for their cellular localization and activity. Collectively, our animal and in vitro findings shed light on the molecular mechanism of statin-induced myopathy and suggest that atrogin-1 may be regulated by novel signaling pathways.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping