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Morroniside ameliorates inflammatory skeletal muscle atrophy via inhibiting canonical and non-canonical NF-κB and regulating protein synthesis/degradation

No drug options exist for skeletal muscle atrophy in clinical, which poses a huge socio-economic burden, making development on drug interventions a general wellbeing need. Patients with a variety of pathologic conditions associated with skeletal muscle atrophy have systemically elevated inflammatory...

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Autores principales: Yi, Xiangjiao, Tao, Jianguo, Qian, Yu, Feng, Feng, Hu, Xueqin, Xu, Taotao, Jin, Hongting, Ruan, Hongfeng, Zheng, Hou-Feng, Tong, Peijian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9816435/
https://www.ncbi.nlm.nih.gov/pubmed/36618945
http://dx.doi.org/10.3389/fphar.2022.1056460
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author Yi, Xiangjiao
Tao, Jianguo
Qian, Yu
Feng, Feng
Hu, Xueqin
Xu, Taotao
Jin, Hongting
Ruan, Hongfeng
Zheng, Hou-Feng
Tong, Peijian
author_facet Yi, Xiangjiao
Tao, Jianguo
Qian, Yu
Feng, Feng
Hu, Xueqin
Xu, Taotao
Jin, Hongting
Ruan, Hongfeng
Zheng, Hou-Feng
Tong, Peijian
author_sort Yi, Xiangjiao
collection PubMed
description No drug options exist for skeletal muscle atrophy in clinical, which poses a huge socio-economic burden, making development on drug interventions a general wellbeing need. Patients with a variety of pathologic conditions associated with skeletal muscle atrophy have systemically elevated inflammatory factors. Morroniside, derived from medicinal herb Cornus officinalis, possesses anti-inflammatory effect. However, whether and how morroniside combat muscle atrophy remain unknown. Here, we identified crucial genetic associations between TNFα/NF-κB pathway and grip strength based on population using 377,807 European participants from the United Kingdom Biobank dataset. Denervation increased TNFα in atrophying skeletal muscles, which inhibited myotube formation in vitro. Notably, morroniside treatment rescued TNFα-induced myotube atrophy in vitro and impeded skeletal muscle atrophy in vivo, resulting in increased body/muscles weights, No. of satellite cells, size of type IIA, IIX and IIB myofibers, and percentage of type IIA myofibers in denervated mice. Mechanistically, in vitro and/or in vivo studies demonstrated that morroniside could not only inhibit canonical and non-canonical NF-κB, inflammatory mediators (IL6, IL-1b, CRP, NIRP3, PTGS2, TNFα), but also down-regulate protein degradation signals (Follistatin, Myostatin, ALK4/5/7, Smad7/3), ubiquitin-proteasome molecules (FoxO3, Atrogin-1, MuRF1), autophagy-lysosomal molecules (Bnip3, LC3A, and LC3B), while promoting protein synthesis signals (IGF-1/IGF-1R/IRS-1/PI3K/Akt, and BMP14/BMPR2/ALK2/3/Smad5/9). Moreover, morroniside had no obvious liver and kidney toxicity. This human genetic, cells and mice pathological evidence indicates that morroniside is an efficacious and safe inflammatory muscle atrophy treatment and suggests its translational potential on muscle wasting.
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spelling pubmed-98164352023-01-07 Morroniside ameliorates inflammatory skeletal muscle atrophy via inhibiting canonical and non-canonical NF-κB and regulating protein synthesis/degradation Yi, Xiangjiao Tao, Jianguo Qian, Yu Feng, Feng Hu, Xueqin Xu, Taotao Jin, Hongting Ruan, Hongfeng Zheng, Hou-Feng Tong, Peijian Front Pharmacol Pharmacology No drug options exist for skeletal muscle atrophy in clinical, which poses a huge socio-economic burden, making development on drug interventions a general wellbeing need. Patients with a variety of pathologic conditions associated with skeletal muscle atrophy have systemically elevated inflammatory factors. Morroniside, derived from medicinal herb Cornus officinalis, possesses anti-inflammatory effect. However, whether and how morroniside combat muscle atrophy remain unknown. Here, we identified crucial genetic associations between TNFα/NF-κB pathway and grip strength based on population using 377,807 European participants from the United Kingdom Biobank dataset. Denervation increased TNFα in atrophying skeletal muscles, which inhibited myotube formation in vitro. Notably, morroniside treatment rescued TNFα-induced myotube atrophy in vitro and impeded skeletal muscle atrophy in vivo, resulting in increased body/muscles weights, No. of satellite cells, size of type IIA, IIX and IIB myofibers, and percentage of type IIA myofibers in denervated mice. Mechanistically, in vitro and/or in vivo studies demonstrated that morroniside could not only inhibit canonical and non-canonical NF-κB, inflammatory mediators (IL6, IL-1b, CRP, NIRP3, PTGS2, TNFα), but also down-regulate protein degradation signals (Follistatin, Myostatin, ALK4/5/7, Smad7/3), ubiquitin-proteasome molecules (FoxO3, Atrogin-1, MuRF1), autophagy-lysosomal molecules (Bnip3, LC3A, and LC3B), while promoting protein synthesis signals (IGF-1/IGF-1R/IRS-1/PI3K/Akt, and BMP14/BMPR2/ALK2/3/Smad5/9). Moreover, morroniside had no obvious liver and kidney toxicity. This human genetic, cells and mice pathological evidence indicates that morroniside is an efficacious and safe inflammatory muscle atrophy treatment and suggests its translational potential on muscle wasting. Frontiers Media S.A. 2022-12-23 /pmc/articles/PMC9816435/ /pubmed/36618945 http://dx.doi.org/10.3389/fphar.2022.1056460 Text en Copyright © 2022 Yi, Tao, Qian, Feng, Hu, Xu, Jin, Ruan, Zheng and Tong. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Yi, Xiangjiao
Tao, Jianguo
Qian, Yu
Feng, Feng
Hu, Xueqin
Xu, Taotao
Jin, Hongting
Ruan, Hongfeng
Zheng, Hou-Feng
Tong, Peijian
Morroniside ameliorates inflammatory skeletal muscle atrophy via inhibiting canonical and non-canonical NF-κB and regulating protein synthesis/degradation
title Morroniside ameliorates inflammatory skeletal muscle atrophy via inhibiting canonical and non-canonical NF-κB and regulating protein synthesis/degradation
title_full Morroniside ameliorates inflammatory skeletal muscle atrophy via inhibiting canonical and non-canonical NF-κB and regulating protein synthesis/degradation
title_fullStr Morroniside ameliorates inflammatory skeletal muscle atrophy via inhibiting canonical and non-canonical NF-κB and regulating protein synthesis/degradation
title_full_unstemmed Morroniside ameliorates inflammatory skeletal muscle atrophy via inhibiting canonical and non-canonical NF-κB and regulating protein synthesis/degradation
title_short Morroniside ameliorates inflammatory skeletal muscle atrophy via inhibiting canonical and non-canonical NF-κB and regulating protein synthesis/degradation
title_sort morroniside ameliorates inflammatory skeletal muscle atrophy via inhibiting canonical and non-canonical nf-κb and regulating protein synthesis/degradation
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9816435/
https://www.ncbi.nlm.nih.gov/pubmed/36618945
http://dx.doi.org/10.3389/fphar.2022.1056460
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