Triptolide induces atrophy of myotubes by triggering IRS-1 degradation and activating the FoxO3 pathway

Wang, Jianfeng; Gao, Xiukui; Ren, Danhong; Zhang, Meihua; Zhang, Pei; Lu, Shengyong; Huan, Caijuan; Yao, Yinan; Zheng, Liling; Bao, Zhenmin; Zhou, Jianying

doi:10.1016/j.tiv.2020.104793

Cited by 9 publications

(4 citation statements)

References 29 publications

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“…The above results all presented a positive outcome by triptolide against inflammation‐induced muscle atrophy. A latest study suggests that higher concentration of triptolide (10–40 nM) induces C2C12 myotubes atrophy by FoxO3 activation (Wang et al, 2020). However, our results demonstrated that 10–100 fM of triptolide possessed anti‐atrophic ability with FoxO3 inactivation.…”

Section: Discussionmentioning

confidence: 99%

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

Fang

Tseng

Lee

et al. 2021

British J Pharmacology

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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.

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Section: Discussionmentioning

confidence: 99%

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

Fang

Tseng

Lee

et al. 2021

British J Pharmacology

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“…We further identified that Klc interacts with and stabilizes IRS1 to promote AKT signaling. Various signal pathways are involved in regulating IRS1 stability 46–53 . Depletion of prolyl carboxypeptidase (PRCP) and prolyl endopeptidase (PREP) induced IRS1 degradation and inhibited PI3K/AKT pathway 46 .…”

Section: Discussionmentioning

confidence: 99%

“…Various signal pathways are involved in regulating IRS1 stability. [46][47][48][49][50][51][52][53] Depletion of prolyl carboxypeptidase (PRCP) and prolyl endopeptidase (PREP) induced IRS1 degradation and inhibited PI3K/AKT pathway. 46 Overexpression of CD36 was also found to stabilize IRS1 levels in C2C12 myotubes.…”

Section: F I G U R Ementioning

confidence: 99%

Kinesin light chain 1 stabilizes insulin receptor substrate 1 to regulate the IGF‐1‐AKT signaling pathway during myoblast differentiation

Qu,

Shi,

et al. 2024

The FASEB Journal

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The IGF signaling pathway plays critical role in regulating skeletal myogenesis. We have demonstrated that KIF5B, the heavy chain of kinesin‐1 motor, promotes myoblast differentiation through regulating IGF‐p38MAPK activation. However, the roles of the kinesin light chain (Klc) in IGF pathway and myoblast differentiation remain elusive. In this study, we found that Klc1 was upregulated during muscle regeneration and downregulated in senescence mouse muscles and dystrophic muscles from mdx (X‐linked muscular dystrophic) mice. Gain‐ and loss‐of‐function experiments further displayed that Klc1 promotes AKT–mTOR activity and positively regulates myogenic differentiation. We further identified that the expression levels of IRS1, the critical node of IGF‐1 signaling, are downregulated in Klc1‐depleted myoblasts. Coimmunoprecipitation study revealed that IRS1 interacted with the 88‐154 amino acid sequence of Klc1 via its PTB domain. Notably, the reduced Klc1 levels were found in senescence and osteoporosis skeletal muscle samples from both mice and human. Taken together, our findings suggested a crucial role of Klc1 in the regulation of IGF‐AKT pathway during myogenesis through stabilizing IRS1, which might ultimately influence the development of muscle‐related disorders.

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“…Noteworthy achievements include effective myotube atrophy management through triptolide, an ingredient isolated from ancient Chinese herbal medicine. This agent triggers IRS-1 degradation and activates the FOXO3 pathway activation (Wang et al, 2020). Furthermore, withaferin A (WFA), a natural protein-specific binding waveform, mitigates nuclear factor kappa B (NF-κB)mediated pro-inflammatory signaling, thereby alleviating cancer cachexia-induced skeletal muscle atrophy (Straughn and Kakar, 2019).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological effects of denervated muscle atrophy due to metabolic imbalance in different periods

QIU,

CHANG,

LIANG

et al. 2023

BIOCELL

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Denervation-induced skeletal muscle atrophy can potentially cause the decline in the quality of life of patients and an increased risk of mortality. Complex pathophysiological mechanisms with dynamic alterations have been documented in skeletal muscle atrophy resulting from innervation loss. Hence, an in-depth comprehension of the key mechanisms and molecules governing skeletal muscle atrophy at varying stages, along with targeted treatment and protection, becomes essential for effective atrophy management. Our preliminary research categorizes the skeletal muscle atrophy process into four stages using microarray analysis. This review extensively discusses the pathways and molecules potentially implicated in regulating the four stages of denervation and muscle atrophy. Notably, drugs targeting the reactivare oxygen species stage and the inflammation stage assume critical roles. Timely intervention during the initial atrophy stages can expedite protection against skeletal muscle atrophy. Additionally, pharmaceutical intervention in the ubiquitin-proteasome pathway associated with atrophy and autophagy lysosomes can effectively slow down skeletal muscle atrophy. Key molecules within this stage encompass MuRF1, MAFbx, LC3II, p62/SQSTM1, etc. This review also compiles a profile of drugs with protective effects against skeletal muscle atrophy at distinct postdenervation stages, thereby augmenting the evidence base for denervation-induced skeletal muscle atrophy treatment.

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Triptolide induces atrophy of myotubes by triggering IRS-1 degradation and activating the FoxO3 pathway

Cited by 9 publications

References 29 publications

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

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

Kinesin light chain 1 stabilizes insulin receptor substrate 1 to regulate the IGF‐1‐AKT signaling pathway during myoblast differentiation

Pharmacological effects of denervated muscle atrophy due to metabolic imbalance in different periods

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