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Necroptosis Mediates Muscle Protein Degradation in a Cachexia Model of Weanling Pig with Lipopolysaccharide Challenge

Necroptosis, an actively researched form of programmed cell death closely related to the inflammatory response, is important in a variety of disorders and diseases. However, the relationship between necroptosis and muscle protein degradation in cachexia is rarely reported. This study aimed to elucid...

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Autores principales: Guo, Junjie, Qin, Xu, Wang, Yang, Li, Xiangen, Wang, Xiuying, Zhu, Huiling, Chen, Shaokui, Zhao, Jiangchao, Xiao, Kan, Liu, Yulan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10341553/
https://www.ncbi.nlm.nih.gov/pubmed/37446099
http://dx.doi.org/10.3390/ijms241310923
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author Guo, Junjie
Qin, Xu
Wang, Yang
Li, Xiangen
Wang, Xiuying
Zhu, Huiling
Chen, Shaokui
Zhao, Jiangchao
Xiao, Kan
Liu, Yulan
author_facet Guo, Junjie
Qin, Xu
Wang, Yang
Li, Xiangen
Wang, Xiuying
Zhu, Huiling
Chen, Shaokui
Zhao, Jiangchao
Xiao, Kan
Liu, Yulan
author_sort Guo, Junjie
collection PubMed
description Necroptosis, an actively researched form of programmed cell death closely related to the inflammatory response, is important in a variety of disorders and diseases. However, the relationship between necroptosis and muscle protein degradation in cachexia is rarely reported. This study aimed to elucidate whether necroptosis played a crucial role in muscle protein degradation in a cachexia model of weaned piglets induced by lipopolysaccharide (LPS). In Experiment 1, the piglets were intraperitoneally injected with LPS to construct the cachexia model, and sacrificed at different time points after LPS injection (1, 2, 4, 8, 12, and 24 h). In Experiment 2, necrostatin-1 (Nec-1), a necroptosis blocker, was pretreated in piglets before the injection of LPS to inhibit the occurrence of necroptosis. Blood and longissimus dorsi muscle samples were collected for further analysis. In the piglet model with LPS-induced cachexia, the morphological and ultrastructural damage, and the release of pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were dynamically elicited in longissimus dorsi muscle. Further, protein concentration and protein/DNA ratio were dynamically decreased, and protein degradation signaling pathway, containing serine/threonine kinase (Akt), Forkhead box O (FOXO), muscular atrophy F-box (MAFbx), and muscle ring finger protein 1 (MuRF1), was dynamically activated in piglets after LPS challenge. Moreover, mRNA and protein expression of necroptosis signals including receptor-interacting protein kinase (RIP)1, RIP3, and mixed lineage kinase domain-like pseudokinase (MLKL), were time-independently upregulated. Subsequently, when Nec-1 was used to inhibit necroptosis, the morphological damage, the increase in expression of pro-inflammatory cytokines, the reduction in protein content and protein/DNA ratio, and the activation of the protein degradation signaling pathway were alleviated. These results provide the first evidence that necroptosis mediates muscle protein degradation in cachexia by LPS challenge.
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spelling pubmed-103415532023-07-14 Necroptosis Mediates Muscle Protein Degradation in a Cachexia Model of Weanling Pig with Lipopolysaccharide Challenge Guo, Junjie Qin, Xu Wang, Yang Li, Xiangen Wang, Xiuying Zhu, Huiling Chen, Shaokui Zhao, Jiangchao Xiao, Kan Liu, Yulan Int J Mol Sci Article Necroptosis, an actively researched form of programmed cell death closely related to the inflammatory response, is important in a variety of disorders and diseases. However, the relationship between necroptosis and muscle protein degradation in cachexia is rarely reported. This study aimed to elucidate whether necroptosis played a crucial role in muscle protein degradation in a cachexia model of weaned piglets induced by lipopolysaccharide (LPS). In Experiment 1, the piglets were intraperitoneally injected with LPS to construct the cachexia model, and sacrificed at different time points after LPS injection (1, 2, 4, 8, 12, and 24 h). In Experiment 2, necrostatin-1 (Nec-1), a necroptosis blocker, was pretreated in piglets before the injection of LPS to inhibit the occurrence of necroptosis. Blood and longissimus dorsi muscle samples were collected for further analysis. In the piglet model with LPS-induced cachexia, the morphological and ultrastructural damage, and the release of pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were dynamically elicited in longissimus dorsi muscle. Further, protein concentration and protein/DNA ratio were dynamically decreased, and protein degradation signaling pathway, containing serine/threonine kinase (Akt), Forkhead box O (FOXO), muscular atrophy F-box (MAFbx), and muscle ring finger protein 1 (MuRF1), was dynamically activated in piglets after LPS challenge. Moreover, mRNA and protein expression of necroptosis signals including receptor-interacting protein kinase (RIP)1, RIP3, and mixed lineage kinase domain-like pseudokinase (MLKL), were time-independently upregulated. Subsequently, when Nec-1 was used to inhibit necroptosis, the morphological damage, the increase in expression of pro-inflammatory cytokines, the reduction in protein content and protein/DNA ratio, and the activation of the protein degradation signaling pathway were alleviated. These results provide the first evidence that necroptosis mediates muscle protein degradation in cachexia by LPS challenge. MDPI 2023-06-30 /pmc/articles/PMC10341553/ /pubmed/37446099 http://dx.doi.org/10.3390/ijms241310923 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Guo, Junjie
Qin, Xu
Wang, Yang
Li, Xiangen
Wang, Xiuying
Zhu, Huiling
Chen, Shaokui
Zhao, Jiangchao
Xiao, Kan
Liu, Yulan
Necroptosis Mediates Muscle Protein Degradation in a Cachexia Model of Weanling Pig with Lipopolysaccharide Challenge
title Necroptosis Mediates Muscle Protein Degradation in a Cachexia Model of Weanling Pig with Lipopolysaccharide Challenge
title_full Necroptosis Mediates Muscle Protein Degradation in a Cachexia Model of Weanling Pig with Lipopolysaccharide Challenge
title_fullStr Necroptosis Mediates Muscle Protein Degradation in a Cachexia Model of Weanling Pig with Lipopolysaccharide Challenge
title_full_unstemmed Necroptosis Mediates Muscle Protein Degradation in a Cachexia Model of Weanling Pig with Lipopolysaccharide Challenge
title_short Necroptosis Mediates Muscle Protein Degradation in a Cachexia Model of Weanling Pig with Lipopolysaccharide Challenge
title_sort necroptosis mediates muscle protein degradation in a cachexia model of weanling pig with lipopolysaccharide challenge
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10341553/
https://www.ncbi.nlm.nih.gov/pubmed/37446099
http://dx.doi.org/10.3390/ijms241310923
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