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SIRT1-dependent mechanisms and effects of resveratrol for amelioration of muscle wasting in NASH mice
  1. Chih-Wei Liu1,2,3,
  2. Chia-Chang Huang3,4,5,
  3. Chien-Fu Hsu2,
  4. Tzu-Hao Li3,5,6,
  5. Yu-Lien Tsai2,
  6. Ming-Wei Lin5,7,
  7. Hung-Cheng Tsai1,2,
  8. Shiang-Fen Huang2,5,8,
  9. Ying-Ying Yang3,4,5,9,
  10. Yun-Cheng Hsieh2,5,9,
  11. Tzung-Yan Lee10,
  12. Chang-Youh Tsai1,2,5,
  13. Yi-Hsiang Huang3,5,9,
  14. Ming-Chih Hou2,5,9,
  15. Han-Chieh Lin2,5,9
  1. 1Division of Allergy, Immunology and Rheumatology, Taipei, Taiwan
  2. 2Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
  3. 3Institute of Clinical Medicine, Taipei, Taiwan
  4. 4Division of Clinical Skills Center, Department of Medical Education, Taipei Veterans General Hospital, Taoyuan, Taiwan
  5. 5Faculty of Medicine, School of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
  6. 6Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
  7. 7Institute of Public Health, School of Medicine, National Yang-Ming University, Taipei, Taiwan
  8. 8Division of Infection Disease, Taipei, Taiwan
  9. 9Division of Gastroenterology and Hepatology, Taipei, Taiwan
  10. 10Graduate Institute of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan
  1. Correspondence to Ying-Ying Yang; yangyy{at}vghtpe.gov.tw

Abstract

Background In non-alcoholic steatohepatitis (NASH), muscle wasting was an aggravating factor for the progression of hepatic steatosis. This study explores the potential benefits of chronic treatment with resveratrol, a strong activator of SIRT1 on the muscle wasting of NASH mice.

Methods In vivo and in vitro study, we evaluate the SIRT1-dependent mechanisms and effects of resveratrol administration for 6 weeks with high-fat-methionine and choline deficient diet-induced NASH mice and palmitate-pretreated C2C12 myoblast cells.

Results Resveratrol treatment improved grip strength and muscle mass of limbs, increased running distance and time on exercise wheels in NASH mice. There is a negative correlation between muscular SIRT1 activity and 3-nitrotyrosine levels of NASH and NASH-resv mice. The SIRT1-dependent effect of muscle wasting was associated with the suppression of oxidative stress, upregulation of antioxidants, inhibition of protein degradation, activation of autophagy, suppression of apoptotic activity, upregulation of lipolytic genes and the reduction of fatty infiltration in limb muscles of NASH mice. In vitro, resveratrol alleviated palmitate acid-induced oxidative stress, lipid deposition, autophagy dysfunction, apoptotic signals, and subsequently reduced fusion index and myotube formation of C2C12 cells. The beneficial effects of resveratrol were abolished by EX527.

Conclusions Our study suggests that chronic resveratrol treatment is a potential strategy for amelioration of hepatic steatosis and muscle wasting in NASH mouse model.

  • apoptosis
  • nonalcoholic steatohepatitis
  • oxidative stress
  • signalling
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Footnotes

  • Contributors C-WL, C-CH, H-CL, and C-FH drafted manuscript; H-CT and Y-LT prepared figures; M-WL, T-HL, and S-FH analysed data; C-WL, Y-YY, and C-CH interpreted results of experiments; C-YT, Y-CH, M-CH, and Y-HH approved final version of manuscript; C-WL, T-YL, S-FH, and Y-YY performed experiments; H-CL and Y-YY conceived and designed research.

  • Funding This work was supported by Ministry of Science and Technology (grant no: MOST-106-2511-S-010–001 -MY3 and MOST-108-2314-B-075-050-MY3) from the National Science Council and Taipei Veterans General Hospital, Taipei, Taiwan (grant no: V106C-007).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval This study was approved by the Animal Experiments Committee of Yang-Ming University and was performed according to the 'Guide for the care and use of laboratory animals' prepared by the National Academy of Science, USA and the ARRIVE guidelines.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article.

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