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  3. A novel oleanolic acid derivative HA-19 ameliorates muscle atrophy via promoting protein synthesis and preventing protein degradation

A novel oleanolic acid derivative HA-19 ameliorates muscle atrophy via promoting protein synthesis and preventing protein degradation

  • Toxicol Appl Pharmacol. 2019 Sep 1;378:114625. doi: 10.1016/j.taap.2019.114625.
Wei Cui 1,  Chen-Xi Liu 1,  Yu-Chao Zhang 1,  Qi Shen 1,  Zhen-Hua Feng 2,  Jie Wang 1,  Sheng-Feng Lu 3,  Jing Wu 4,  Jian-Xin Li 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Analytical Chemistry for Life Science, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.
  • 2 The Center of Diagnosis and Treatment for Joint Disease, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing 210008, China.
  • 3 Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 4 State Key Laboratory of Analytical Chemistry for Life Science, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China. Electronic address: wujnju@nju.edu.cn.
  • 5 State Key Laboratory of Analytical Chemistry for Life Science, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China. Electronic address: lijxnju@nju.edu.cn.
PMID: 31201822 DOI: 10.1016/j.taap.2019.114625
Abstract

Muscle atrophy refers to a decrease in the size of muscles in the body, occurs in certain muscles with inactivity in many diseases and lacks effective therapies up to date. Natural Products still play an important role in drug discovery. In the present study, derivatives of a natural product, oleanolic acid, were screened with myoblast differentiation and myotube atrophy assays, respectively. Results revealed that one of the derivatives, HA-19 showed the most potent anti-muscle atrophy activity, and was used for further studies. We demonstrated that HA-19 led to the increase of the protein synthesis by activating mechanistic target of rapamycin complex 1 (mTORC1)/p70 S6K pathways, and also enhanced myoblast proliferation and terminal differentiation via up-regulating of the myogenic transcription factors Pax7, MyoD and Myogenin. The interesting thing was that HA-19 also suppressed protein degradation to prevent myotube atrophy by down-regulating negative growth factors, FoxO1, MuRF1 and Atrogin-1. The results were also supported by puromycin labelling and protein ubiquitination assays. These data revealed that HA-19 possessed a "dual effect" on inhibition of muscle atrophy. In disuse-induced muscle atrophy mice model, HA-19 treatment significantly increased the weights of bilateral tibialis anterior (TA), gastrocnemius (Gastroc.), quadriceps (Quad.), suggesting the effectiveness of HA-19 to remit disuse-induced muscle atrophy. Our finding demonstrated that HA-19 has a great potential as an inhibitor or lead compound for the anti-muscle atrophy drug discovery.

Keywords

HA-19; Muscle atrophy; Muscle regeneration; Protein degradation; Protein synthesis.

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