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. 2021 Aug;178(15):2998-3016.
doi: 10.1111/bph.15472. Epub 2021 May 21.

Triptolide prevents LPS-induced skeletal muscle atrophy via inhibiting NF-κB/TNF-α and regulating protein synthesis/degradation pathway

Wei-Yu Fang  1 , Yu-Ting Tseng  1   2 , Tzu-Ying Lee  1 , Yin-Chih Fu  3   4 , Wan-Hsuan Chang  1   5 , Wan-Wen Lo  1   5 , Chih-Lung Lin  6   7 , Yi-Ching Lo  1   5   8   9
Affiliations
Free article

Triptolide prevents LPS-induced skeletal muscle atrophy via inhibiting NF-κB/TNF-α and regulating protein synthesis/degradation pathway

Wei-Yu Fang et al. Br J Pharmacol. 2021 Aug.
Free article

Abstract

Background and purpose: Increasing evidence suggests systemic inflammation-caused skeletal muscle atrophy as a major clinical feature of cachexia. Triptolide obtained from Tripterygium wilfordii Hook F possesses potent anti-inflammatory and immunosuppressive effects. The present study aims to evaluate the protective effects and molecular mechanisms of triptolide on inflammation-induced skeletal muscle atrophy.

Experimental approach: The effects of triptolide on skeletal muscle atrophy were investigated in LPS-treated C2C12 myotubes and C57BL/6 mice. Protein expressions and mRNA levels were analysed by western blot and qPCR, respectively. Skeletal muscle mass, volume and strength were measured by histological analysis, micro-CT and grip strength, respectively. Locomotor activity was measured using the open field test.

Key results: Triptolide (10-100 fM) up-regulated protein synthesis signals (IGF-1/p-IGF-1R/IRS-1/p-Akt/p-mTOR) and down-regulated protein degradation signal atrogin-1 in C2C12 myotubes. In LPS (100 ng·ml-1 )-treated C2C12 myotubes, triptolide up-regulated MyHC, IGF-1, p-IGF-1R, IRS-1 and p-Akt. Triptolide also down-regulated ubiquitin-proteasome molecules (n-FoxO3a/atrogin-1/MuRF1), proteasome activity, autophagy-lysosomal molecules (LC3-II/LC3-I and Bnip3) and inflammatory mediators (NF-κB, Cox-2, NLRP3, IL-1β and TNF-α). However, AG1024, an IGF-1R inhibitor, suppressed triptolide-mediated effects on MyHC, myotube diameter, MuRF1 and p62 in LPS-treated C2C12 myotubes. In LPS (1 mg·kg-1 , i.p.)-challenged mice, triptolide (5 and 20 μg·kg-1 ·day-1 , i.p.) decreased plasma TNF-α levels and it increased skeletal muscle volume, cross-sectional area of myofibers, weights of the gastrocnemius and tibialis anterior muscles, forelimb grip strength and locomotion.

Conclusions and implications: These findings reveal that triptolide prevented LPS-induced inflammation and skeletal muscle atrophy and have implications for the discovery of novel agents for preventing muscle wasting.

Keywords: anti-inflammation; autophagy-lysosomal pathway; insulin-like growth factor 1; skeletal muscle atrophy; triptolide; ubiquitin-proteasome system.

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