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Skeletal muscle-specific HMG-CoA reductase knockout mice exhibit rhabdomyolysis: A model for statin-induced myopathy.

Abstract
HMG-CoA reductase (HMGCR) catalyzes the conversion of HMG-CoA to mevalonic acid (MVA); this is the rate-limiting enzyme of the mevalonate pathway that synthesizes cholesterol. Statins, HMGCR inhibitors, are widely used as cholesterol-reducing drugs. However, statin-induced myopathy is the most adverse side effect of statins. To eludicate the mechanisms underlying statin the myotoxicity and HMGCR function in the skeletal muscle, we developed the skeletal muscle-specific HMGCR knockout mice. Knockout mice exhibited postnatal myopathy with elevated serum creatine kinase levels and necrosis. Myopathy in knockout mice was completely rescued by the oral administration of MVA. These results suggest that skeletal muscle toxicity caused by statins is dependent on the deficiencies of HMGCR enzyme activity and downstream metabolites of the mevalonate pathway in skeletal muscles rather than the liver or other organs.
AuthorsYoshinori Osaki, Yoshimi Nakagawa, Shoko Miyahara, Hitoshi Iwasaki, Akiko Ishii, Takashi Matsuzaka, Kazuto Kobayashi, Shigeru Yatoh, Akimitsu Takahashi, Naoya Yahagi, Hiroaki Suzuki, Hirohito Sone, Ken Ohashi, Shun Ishibashi, Nobuhiro Yamada, Hitoshi Shimano
JournalBiochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 466 Issue 3 Pg. 536-40 (Oct 23 2015) ISSN: 1090-2104 [Electronic] United States
PMID26381177 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 Elsevier Inc. All rights reserved.
Chemical References
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • RNA, Messenger
  • Cholesterol
  • Hydroxymethylglutaryl CoA Reductases
  • Creatine Kinase
  • Mevalonic Acid
Topics
  • Animals
  • Cholesterol (metabolism)
  • Creatine Kinase (blood)
  • Disease Models, Animal
  • Hydroxymethylglutaryl CoA Reductases (deficiency, genetics, metabolism)
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors (adverse effects)
  • Male
  • Mevalonic Acid (metabolism)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Skeletal (enzymology)
  • Muscular Diseases (chemically induced, enzymology)
  • RNA, Messenger (genetics, metabolism)
  • Rhabdomyolysis (enzymology, etiology)

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