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other·preclinical research, animal science, biomedical research, nutrition, immunology·PMC10341553

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

International Journal of Molecular Sciences · 10 authors, 3 centres

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TL;DR

This study used a lipopolysaccharide (LPS)-challenged weanling pig model to investigate muscle wasting in cachexia. The central result was that inhibiting the cell death process necroptosis with Nec-1 alleviated LPS-induced muscle inflammation and protein degradation.

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This preclinical study used weanling pigs to model cachexia induced by LPS injection. Researchers measured plasma hormone markers, muscle morphology, and molecular pathways at various time points after LPS challenge. They found LPS triggered a systemic inflammatory response, activated the Akt/FOXO/UPS muscle protein degradation pathway, and upregulated necroptosis markers (RIP1, RIP3, MLKL) in muscle. Pretreatment with the necroptosis inhibitor Nec-1 reversed LPS-induced upregulation of necroptosis markers, attenuated muscle morphological damage, reduced inflammation, and alleviated the reduction in muscle protein content and key degradation gene expression. The implications suggest necroptosis is a potential target for treating muscle wasting in cachexia.

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other

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preclinical research

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ORIGINAL PAPER

PMC10341553

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

International Journal of Molecular Sciences

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ABSTRACT

Abstract 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. Keywords: necroptosis, cachexia, pro-inflammatory cytokines, protein degradation

CITATION EXPORT

Junjie Guo, Xu Qin, Yang Wang et al.. Necroptosis Mediates Muscle Protein Degradation in a Cachexia Model of Weanling Pig with Lipopolysaccharide Challenge. International Journal of Molecular Sciences. (2023). https://doi.org/10.3390/ijms241310923

AUTHORS

10 · 3 CENTRES

Junjie Guo, Xu Qin, Yang Wang, Xiangen Li, Xiuying Wang, Huiling Zhu, Shaokui Chen, Jiangchao Zhao, Kan Xiao, Yulan Liu

1Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China; [email protected] (J.G.); [email protected] (X.Q.); [email protected] (Y.W.); [email protected] (X.L.); [email protected] (X.W.); [email protected] (H.Z.); [email protected] (S.C.)
2Department of Animal Science, Division of Agriculture, University of Arkansas, Fayetteville, AR 72701, USA; [email protected]
3School of Animal Science and Nutritional Engineering, Wuhan Polytechnic University, No. 68 Xuefu South Rd., Wuhan 430023, China