The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity
Jun-ichi Hanai, Peirang Cao, Preeti Tanksale, Shintaro Imamura, Eriko Koshimizu, Jinghui Zhao, Shuji Kishi, Michiaki Yamashita, Paul S Phillips, Vikas P Sukhatme, Stewart H Lecker, Jun-ichi Hanai, Peirang Cao, Preeti Tanksale, Shintaro Imamura, Eriko Koshimizu, Jinghui Zhao, Shuji Kishi, Michiaki Yamashita, Paul S Phillips, Vikas P Sukhatme, Stewart H Lecker
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.
Figures
![Figure 1. Atrogin-1 is induced in human…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2096469/bin/JCI0732741.f1.jpg)
![Figure 2. Lovastatin causes reduction in myotube…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2096469/bin/JCI0732741.f2.jpg)
![Figure 3. Lovastatin induces expression of both…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2096469/bin/JCI0732741.f3.jpg)
![Figure 4. Myotubes from atrogin-1 null (–/–)…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2096469/bin/JCI0732741.f4.jpg)
![Figure 5. Lovastatin treatment disrupts myofiber structure…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2096469/bin/JCI0732741.f5.jpg)
![Figure 6. Targeted knockdown of zebrafish HMG-CoA…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2096469/bin/JCI0732741.f6.jpg)
![Figure 7. Atrogin-1 knockdown reduces lovastatin-induced muscle…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2096469/bin/JCI0732741.f7.jpg)
![Figure 8. Lovastatin suppresses IGF-1 signaling.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2096469/bin/JCI0732741.f8.jpg)
![Figure 9. PGC-1α expression reduces lovastatin-induced atrogin-1…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2096469/bin/JCI0732741.f9.jpg)
![Figure 10. PGC-1α reduces lovastatin-induced atrogin-1 expression…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2096469/bin/JCI0732741.f10.jpg)
Source: PubMed