PUBLICATION
The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity
- Authors
- Hanai, J.I., Cao, P., Tanksale, P., Imamura, S., Koshimizu, E., Zhao, J., Kishi, S., Yamashita, M., Phillips, P.S., Sukhatme, V.P., and Lecker, S.H.
- ID
- ZDB-PUB-071118-40
- Date
- 2007
- Source
- J. Clin. Invest. 117(12): 3940-3951 (Journal)
- Registered Authors
- Kishi, Shuji, Sukhatme, Vikas, Yamashita, Michiaki
- Keywords
- none
- MeSH Terms
-
- Animals
- Cholesterol/metabolism
- Heat-Shock Proteins/genetics
- Heat-Shock Proteins/metabolism
- Humans
- Hydroxymethylglutaryl CoA Reductases/genetics
- Hydroxymethylglutaryl CoA Reductases/metabolism
- Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects*
- Lovastatin/adverse effects*
- Mice
- Muscle Fibers, Skeletal/enzymology
- Muscle Fibers, Skeletal/pathology
- Muscle Proteins/genetics
- Muscle Proteins/metabolism*
- Muscle, Skeletal/enzymology
- Muscle, Skeletal/pathology
- Muscular Disorders, Atrophic/chemically induced
- Muscular Disorders, Atrophic/enzymology*
- Muscular Disorders, Atrophic/genetics
- Muscular Disorders, Atrophic/pathology
- SKP Cullin F-Box Protein Ligases/genetics
- SKP Cullin F-Box Protein Ligases/metabolism*
- Trans-Activators/genetics
- Trans-Activators/metabolism*
- Transcription Factors/genetics
- Transcription Factors/metabolism
- Zebrafish/genetics
- Zebrafish/metabolism*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 17992259 Full text @ J. Clin. Invest.
Citation
Hanai, J.I., Cao, P., Tanksale, P., Imamura, S., Koshimizu, E., Zhao, J., Kishi, S., Yamashita, M., Phillips, P.S., Sukhatme, V.P., and Lecker, S.H. (2007) The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity. J. Clin. Invest.. 117(12):3940-3951.
Abstract
Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, and are widely used to treat hypercholesterolemia. These drugs can lead to a number of side effects in muscle, including muscle fiber breakdown; however, the mechanisms of muscle injury by statins are poorly understood. We report that lovastatin induced the expression of atrogin-1, a key gene involved in skeletal muscle atrophy, in humans with statin myopathy, in zebrafish embryos, and in vitro in murine skeletal muscle cells. In cultured mouse myotubes, atrogin-1 induction following lovastatin treatment was accompanied by distinct morphological changes, largely absent in atrogin-1 null cells. In zebrafish embryos, lovastatin promoted muscle fiber damage, an effect that was closely mimicked by knockdown of zebrafish HMG-CoA reductase. Moreover, atrogin-1 knockdown in zebrafish embryos prevented lovastatin-induced muscle injury. Finally, overexpression of PGC-1alpha, a transcriptional coactivator that induces mitochondrial biogenesis and protects against the development of muscle atrophy, dramatically prevented lovastatin-induced muscle damage and abrogated atrogin-1 induction both in fish and in cultured mouse myotubes. Collectively, our human, animal, and in vitro findings shed light on the molecular mechanism of statin-induced myopathy and suggest that atrogin-1 may be a critical mediator of the muscle damage induced by statins.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping