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

Yoshinori 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

doi:10.1016/j.bbrc.2015.09.065

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

Yoshinori 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^*

^*Corresponding author for this work

Complex Biosystem Research, Institute of Natural Medicine

Research output: Contribution to journal › Article › peer-review

72 Scopus citations

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.

Original language	English
Pages (from-to)	536-540
Number of pages	5
Journal	Biochemical and Biophysical Research Communications
Volume	466
Issue number	3
DOIs	https://doi.org/10.1016/j.bbrc.2015.09.065
State	Published - 2015/10/23

Keywords

HMG-CoA reductase
Knockout mice
Mevalonic acid
Necrosis
Rhabdomyolysis
Skeletal muscle

ASJC Scopus subject areas

Biophysics
Biochemistry
Molecular Biology
Cell Biology

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Osaki, Y., Nakagawa, Y., Miyahara, S., Iwasaki, H., Ishii, A., Matsuzaka, T., Kobayashi, K., Yatoh, S., Takahashi, A., Yahagi, N., Suzuki, H., Sone, H., Ohashi, K., Ishibashi, S., Yamada, N., & Shimano, H. (2015). Skeletal muscle-specific HMG-CoA reductase knockout mice exhibit rhabdomyolysis: A model for statin-induced myopathy. Biochemical and Biophysical Research Communications, 466(3), 536-540. https://doi.org/10.1016/j.bbrc.2015.09.065

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title = "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.",

keywords = "HMG-CoA reductase, Knockout mice, Mevalonic acid, Necrosis, Rhabdomyolysis, Skeletal muscle",

author = "Yoshinori Osaki and Yoshimi Nakagawa and Shoko Miyahara and Hitoshi Iwasaki and Akiko Ishii and Takashi Matsuzaka and Kazuto Kobayashi and Shigeru Yatoh and Akimitsu Takahashi and Naoya Yahagi and Hiroaki Suzuki and Hirohito Sone and Ken Ohashi and Shun Ishibashi and Nobuhiro Yamada and Hitoshi Shimano",

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

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doi = "10.1016/j.bbrc.2015.09.065",

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Osaki, Y, Nakagawa, Y, Miyahara, S, Iwasaki, H, Ishii, A, Matsuzaka, T, Kobayashi, K, Yatoh, S, Takahashi, A, Yahagi, N, Suzuki, H, Sone, H, Ohashi, K, Ishibashi, S, Yamada, N & Shimano, H 2015, 'Skeletal muscle-specific HMG-CoA reductase knockout mice exhibit rhabdomyolysis: A model for statin-induced myopathy', Biochemical and Biophysical Research Communications, vol. 466, no. 3, pp. 536-540. https://doi.org/10.1016/j.bbrc.2015.09.065

TY - JOUR

T1 - Skeletal muscle-specific HMG-CoA reductase knockout mice exhibit rhabdomyolysis

T2 - A model for statin-induced myopathy

AU - Osaki, Yoshinori

AU - Nakagawa, Yoshimi

AU - Miyahara, Shoko

AU - Iwasaki, Hitoshi

AU - Ishii, Akiko

AU - Matsuzaka, Takashi

AU - Kobayashi, Kazuto

AU - Yatoh, Shigeru

AU - Takahashi, Akimitsu

AU - Yahagi, Naoya

AU - Suzuki, Hiroaki

AU - Sone, Hirohito

AU - Ohashi, Ken

AU - Ishibashi, Shun

AU - Yamada, Nobuhiro

AU - Shimano, Hitoshi

PY - 2015/10/23

Y1 - 2015/10/23

N2 - 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.

AB - 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.

KW - HMG-CoA reductase

KW - Knockout mice

KW - Mevalonic acid

KW - Necrosis

KW - Rhabdomyolysis

KW - Skeletal muscle

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U2 - 10.1016/j.bbrc.2015.09.065

DO - 10.1016/j.bbrc.2015.09.065

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C2 - 26381177

AN - SCOPUS:84952637961

SN - 0006-291X

VL - 466

SP - 536

EP - 540

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

IS - 3

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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