Molecular mechanism of autophagic abnormality in mouse model with rhabdomyolysis

• Project/Area Number: 15K15344
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Metabolomics
• Research Institution: University of Tsukuba
• Principal Investigator: SHIMANO Hitoshi 筑波大学, 医学医療系, 教授 (20251241)
• Co-Investigator(Kenkyū-buntansha): 中川 嘉 筑波大学, 国際統合睡眠医科学研究機構, 准教授 (80361351)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: スタチン / 横紋筋融解症 / オートファジー / コレステロール / コレステロール合成系 / HMGCR / コレステロール合成

Outline of Final Research Achievements

This study was aimed to elucidate the mechanism of the onset of rhabdomyolysis, which is a side effect of statin which is a treatment for hypercholesterolemia. We generated skeletal muscle specific-HMGCR, a target of statin, knockout mice. The turnover between cell death and regeneration were frequently occurred in muscle cells of mKO mice, indicating that the deficiency of HMGCR in skeletal muscle leads to myopathy. We examined the relationship between myopathy and autophagy in skeletal muscle of these mice. The function of Rab7, which is involved in the formation of autolysosomes, was impaired and the degradation of autolysosomes was he also impaired in skeletal muscle of these mice. Thus, we found that the skeletal muscle cells of mKO mice exhibited the abnormality of autolysosomes and the increase of p62 protein, due to the functional abnormality of lysosome.

Research Products

• [Journal Article] Skeletal muscle-specific HMG-CoA reductase knockout mice exhibit rhabdomyolysis: A model for statin-induced myopathy. (2015)
  • Author(s): 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
  • Journal Title: Biochem Biophys Res Commun. Volume: 466(3) Issue: 3 Pages: 536-540
  • DOI: 10.1016/j.bbrc.2015.09.065
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Remarks] 筑波大学 医学医療系 内分泌代謝・糖尿病内科
  • URL: http://www.u-tsukuba-endocrinology.jp/