Glutamate alleviates muscle protein loss by modulating TLR4, NODs, Akt/FOXO and mTOR signaling pathways in LPS-challenged piglets.

Ping Kang,Xiuying Wang,Yulan Liu,Huiling Zhu,Longmei Wang,Yongqing Hou,Huanting Wu,Cristoforo Scavone

doi:10.1371/journal.pone.0182246

Ping Kang, Xiuying Wang + Show 6 more

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https://doi.org/10.1371/journal.pone.0182246

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Journal: PloS one	Publication Date: Aug 4, 2017
Citations: 13	License type: CC BY 4.0

Affiliation: Wuhan Polytechnic University

Abstract

The experiment was conducted to study the effect of the glutamate (Glu) on muscle protein loss through toll-like receptor 4 (TLR4), nucleotide-binding oligomerization domain proteins (NODs), Akt/Forkhead Box O (Akt/FOXO) and mammalian target of rapamycin (mTOR) signaling pathways in LPS-challenged piglets. Twenty-four weaned piglets were assigned into four treatments: (1) Control; (2) LPS+0% Glu; (3) LPS + 1.0% Glu; (4) LPS + 2.0% Glu. The experiment was lasted for 28 days. On d 28, the piglets in the LPS challenged groups were injected with LPS on 100 μg/kg body weight (BW), and the piglets in the control group were injected with the same volume of 0.9% NaCl solution. After 4 h LPS or saline injection, the piglets were slaughtered and the muscle samples were collected. Glu supplementation increased the protein/DNA ratio in gastrocnemius muscle, and the protein content in longissimus dorsi (LD) muscle after LPS challenge (P<0.05). In addition, Glu supplementation decreased TLR4, IL-1 receptor-associated kinase (IRAK) 1, receptor-interacting serine/threonine-protein kinase (RIPK) 2, and nuclear factor-κB (NF-κB) mRNA expression in gastrocnemius muscle (P<0.05), MyD88 mRNA expression in LD muscle, and FOXO1 mRNA expression in LD muscle (P<0.05). Moreover, Glu supplementation increased p-Akt/t-Akt ratio (P<0.05) in gastrocnemius muscle, and p-4EBP1/t-4EBP1 ratio in both gastrocnemius and LD muscles (P<0.05). Glu supplementation in the piglets’ diets might be an effective strategy to alleviate LPS-induced muscle protein loss, which might be due to suppressing the mRNA expression of TLR4 and NODs signaling-related genes, and modulating Akt/FOXO and mTOR signaling pathways.

Highlights

Toll-like receptor (TLR) 4 as a key component of the innate immunity is present in skeletal muscle [1]
In consistent with Frisard et al (2015) [41] who found that LPS challenge stimulated toll-like receptor 4 (TLR4) activation in skeletal muscle, we found LPS injection up-regulated TLR4 mRNA expression, which further increased MyD88 mRNA expression in gastrocnemius muscle
Glu inclusion decreased nuclear factor-κB (NF-κB) and RIPK2 mRNA expression in gastrocnemius muscle. These results indicates that Glu supplementation had a positive effect on alleviating muscle protein degradation partially by suppressing the mRNA expression of TLR4 and nucleotide-binding oligomerization domain proteins (NODs) signaling-related genes after LPS challenge

Summary

Introduction

Toll-like receptor (TLR) 4 as a key component of the innate immunity is present in skeletal muscle [1]. Myeloid differentiation factor (MyD) 88 [2,3], interacts with TLR4 to initiate nuclear factor-κB (NF-κB), which up-regulates the expression of the genes encoding pro-inflammatory cytokines during LPS challenge. Glutamate alleviates muscle protein loss nucleotide-binding oligomerization domain protein (NOD) 1 and NOD 2 can activate NF-κB to release pro-inflammatory cytokines [4,5,6]. Pro-inflammatory cytokines can lead to muscle atrophy partially via changing the Akt / Forkhead Box O (FOXO)/ubiquitin-proteasome proteolysis (UPP) pathway [10]. UPP is the primary proteolytic system, which can degrade most cell proteins [12] and contribute to 75% protein degradation during skeletal muscle atrophy [13,14]. Many evidences have shown that mammalian target of rapamycin (mTOR) pathway plays a very crucial role on protein synthesis

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