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

Abstract

Background and Purpose: Increasing evidence suggests systemic inflammationcaused 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 ngÁml À1 )-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 mgÁkg À1 , i.p.)-challenged mice, triptolide (5 and 20 μgÁkg À1 Áday À1 , 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.

Walking down Skeletal Muscle Lane: From Inflammasome to Disease

“…NF-κB mediators have shown interesting results in skeletal muscle inflammatory models. As previously explained, triptolide prevented muscle atrophy in LPS challenged mice [ 129 ], carbenoxolone was able to decrease metabolic abnormalities, such as liver and muscle steatosis, in HFD-mice [ 100 ], while melatonin showed an interesting anti-inflammatory effect and preserved the normal muscular structure and activity in a sarcopenic mouse model [ 116 , 117 , 118 , 183 ]. Curcumin was shown to decrease ROS levels and proinflammatory cytokines in C2C12 muscle cells submitted to palmitate induced inflammation [ 184 ], and to improve the dystrophic phenotype in mdx mice [ 145 ].…”

“…Likewise, Triptolide, a plant derivative previously described as an NLRP3 inhibitor [ 128 ], attenuated LPS-induced myotube atrophy in vitro in C2C12 cells and in vivo in LPS injected mice. Thus, triptolide decreased plasma inflammation while increasing skeletal muscle weight, strength and locomotion, thereby preventing muscle atrophy in LPS challenged mice [ 129 ]. OLT1177, an orally active β-sulfonyl nitrile molecule targeting the NLRP3 NACHT domain, was also shown to reduce the severity of systemic inflammation in mice challenged with LPS, where muscle IL-1β and oxidative stress were lowered [ 130 ].…”

Rifaximin enhances the L‑carnitine‑mediated preventive effects on skeletal muscle atrophy in cirrhotic rats by modulating the gut‑liver‑muscle axis

“…Given that TNF-α is a key mediator of liver fibrosis-induced muscle atrophy, the rifaximin-mediated anti-sarcopenic effect was also relevant to the improved hepatic pathology ( 40 ). Previous studies have documented that an LPS stimulus decreases the circulating levels and hepatic expression of IGF-1, and leads to the inhibition of skeletal muscle protein synthesis ( 41 , 42 ). In the present study, the CDAA-fed rats exhibited a reduction in both serum and hepatic levels of IGF-1 along with the hepatic overload of LPS.…”

Effects of Oral Glucose-Lowering Agents on Gut Microbiota and Microbial Metabolites

“…This contradiction might be explained by the fact that the LPS produced by the Bacteroidetes phylum has a lower endotoxic activity than other gram-negative bacteria such as the Proteobacteria phylum ( 55 ). Subsequently, a high concentration of LPS produced within the gut (metabolic endotoxemia) might lead to chronic low-grade inflammation in diabetic subjects through upregulating inflammatory signaling pathways and proinflammatory cytokine secretion ( 56 , 57 ). LPSs produced by gut bacteria might damage the intestinal barrier leading to a “leaky gut” syndrome, for instance, a weakened tight junction and reduced gut secretory immunoglobulin A ( 58 ).…”