Nutrition Research and Practice

The Korean Nutrition Society (한국영양학회)
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Ursolic acid improves the indoxyl sulfate-induced impairment of mitochondrial biogenesis in C2C12 cells

  • Sasaki, Yutaro (Department of Nutrition, Faculty of Health Science, Aomori University of Health and Welfare) ;
  • Kojima-Yuasa, Akiko (Department of Food and Human Health Sciences, Graduate School of Human Life & Science, Osaka City University) ;
  • Tadano, Hinako (Department of Nutrition, Faculty of Health Science, Aomori University of Health and Welfare) ;
  • Mizuno, Ayaka (Department of Nutrition, Faculty of Health Science, Aomori University of Health and Welfare) ;
  • Kon, Atsushi (Department of Nutrition, Faculty of Health Science, Aomori University of Health and Welfare) ;
  • Norikura, Toshio (Department of Nutrition, Faculty of Health Science, Aomori University of Health and Welfare)
  • Received : 2021.03.30
  • Accepted : 2021.07.08
  • Published : 2022.04.01
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Abstract

BACKGROUND/OBJECTIVES: Patients with chronic kidney disease (CKD) have a high concentration of uremic toxins in their blood and often experience muscle atrophy. Indoxyl sulfate (IS) is a uremic toxin produced by tryptophan metabolism. Although an elevated IS level may induce muscle dysfunction, the effect of IS on physiological concentration has not been elucidated. Additionally, the effects of ursolic acid (UA) on muscle hypertrophy have been reported in healthy models; however, it is unclear whether UA ameliorates muscle dysfunction associated with chronic diseases, such as CKD. Thus, this study aimed to investigate whether UA can improve the IS-induced impairment of mitochondrial biogenesis. MATERIALS/METHODS: C2C12 cells were incubated with or without IS (0.1 mM) and UA (1 or 2 μM) to elucidate the physiological effect of UA on CKD-related mitochondrial dysfunction and its related mechanisms using real-time reverse transcription-polymerase chain reaction, western blotting and enzyme-linked immunosorbent assay. RESULTS: IS suppressed the expression of differentiation marker genes without decreasing cell viability. IS decreased the mitochondrial DNA copy number and ATP levels by downregulating the genes pertaining to mitochondrial biogenesis (Ppargc1a, Nrf1, Tfam, Sirt1, and Mef2c), fusion (Mfn1 and Mfn2), oxidative phosphorylation (Cycs and Atp5b), and fatty acid oxidation (Pdk4, Acadm, Cpt1b, and Cd36). Furthermore, IS increased the intracellular mRNA and secretory protein levels of interleukin (IL)-6. Finally, UA ameliorated the IS-induced impairment in C2C12 cells. CONCLUSIONS: Our results indicated that UA improves the IS-induced impairment of mitochondrial biogenesis by affecting differentiation, ATP levels, and IL-6 secretion in C2C12 cells. Therefore, UA could be a novel therapeutic agent for CKD-induced muscle dysfunction.

Keywords

Acknowledgement

We would like to thank Editage (http://www.editage.jp) for English language editing.

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