Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity
Jun-ichi Hanai, … , Vikas P. Sukhatme, Stewart H. Lecker
Jun-ichi Hanai, … , Vikas P. Sukhatme, Stewart H. Lecker
Published November 8, 2007
Citation Information: J Clin Invest. 2007;117(12):3940-3951. https://doi.org/10.1172/JCI32741.
View: Text | PDF
Research Article Cardiology

The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity

  • Text
  • PDF
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-1α, 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.

Authors

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

×

Figure 8

Lovastatin suppresses IGF-1 signaling.

Options: View larger image (or click on image) Download as PowerPoint
Lovastatin suppresses IGF-1 signaling.
(A) Lovastatin suppresses PI3K/AK...
(A) Lovastatin suppresses PI3K/AKT/FoxO signaling in C2C12 myotubes. C2C12 myotubes were treated for 24 hours with vehicle (v) or lovastatin at the indicated concentrations. Protein lysates were prepared and subjected to immunoblot analysis with various antibodies. (B) Lovastatin induces the atrogin-1 promoter in a FoxO-dependent manner in zebrafish embryos. Embryos at the 1-cell stage were injected with the 0.4-kb atrogin-1 promoter reporter with the FoxO sites present or mutated (45). Embryos were grown in the presence of 0.5 μM lovastatin and luciferase activity measured in embryo lysates 48 hours later. Constitutively active FoxO3a was coinjected as a positive control.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts