Aspartate inhibits LPS-induced MAFbx and MuRF1 expression in skeletal muscle in weaned pigs by regulating Akt, AMPKα and FOXO1

Liu, Yulan; Wang, Xiuying; Leng, Weibo; Pi, Dingan; Tu, Zhixiao; Zhu, Huiling; Shi, Haifeng; Li, Shuang; Hou, Yongqing; Hu, Chien‐An Andy

doi:10.1177/1753425916673443

Cited by 10 publications

(8 citation statements)

References 45 publications

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“…We note up‐regulation of E3 ligases Atrogin1 and MuRF1 4 weeks following tumour implantation with concomitantly significantly increased protein ubiquitination. This increase in the ubiquitin‐proteasome system likely occurs through enhanced FOXO1 content, which is responsible for promoting the expression of atrogenes such as Atrogin1 and MuRF1 …”

Section: Discussionmentioning

confidence: 99%

Protein imbalance in the development of skeletal muscle wasting in tumour‐bearing mice

Brown

Lee

Rosa‐Caldwell

et al. 2018

J cachexia sarcopenia muscle

135

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BackgroundCancer cachexia occurs in approximately 80% of cancer patients and is a key contributor to cancer‐related death. The mechanisms controlling development of tumour‐induced muscle wasting are not fully elucidated. Specifically, the progression and development of cancer cachexia are underexplored. Therefore, we examined skeletal muscle protein turnover throughout the development of cancer cachexia in tumour‐bearing mice.MethodsLewis lung carcinoma (LLC) was injected into the hind flank of C57BL6/J mice at 8 weeks age with tumour allowed to develop for 1, 2, 3, or 4 weeks and compared with PBS injected control. Muscle size was measured by cross‐sectional area analysis of haematoxylin and eosin stained tibialis anterior muscle. 2H2O was used to assess protein synthesis throughout the development of cancer cachexia. Immunoblot and RT‐qPCR were used to measure regulators of protein turnover. TUNEL staining was utilized to measure apoptotic nuclei. LLC conditioned media (LCM) treatment of C2C12 myotubes was used to analyse cancer cachexia in vitro.ResultsMuscle cross‐sectional area decreased ~40% 4 weeks following tumour implantation. Myogenic signalling was suppressed in tumour‐bearing mice as soon as 1 week following tumour implantation, including lower mRNA contents of Pax7, MyoD, CyclinD1, and Myogenin, when compared with control animals. AchRδ and AchRε mRNA contents were down‐regulated by ~50% 3 weeks following tumour implantation. Mixed fractional synthesis rate protein synthesis was ~40% lower in 4 week tumour‐bearing mice when compared with PBS controls. Protein ubiquitination was elevated by ~50% 4 weeks after tumour implantation. Moreover, there was an increase in autophagy machinery after 4 weeks of tumour growth. Finally, ERK and p38 MAPK phosphorylations were fourfold and threefold greater than control muscle 4 weeks following tumour implantation, respectively. Inhibition of p38 MAPK, but not ERK MAPK, in vitro partially rescued LCM‐induced loss of myotube diameter.ConclusionsOur findings work towards understanding the pathophysiological signalling in skeletal muscle in the initial development of cancer cachexia. Shortly following the onset of the tumour‐bearing state alterations in myogenic regulatory factors are apparent, suggesting early onset alterations in the capacity for myogenic induction. Cancer cachexia presents with a combination of a loss of protein synthesis and increased markers of protein breakdown, specifically in the ubiquitin‐proteasome system. Also, p38 MAPK may be a potential therapeutic target to combat cancer cachexia via a p38‐FOX01‐atrogene‐ubiquitin‐proteasome mechanism.

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Section: Discussionmentioning

confidence: 99%

Protein imbalance in the development of skeletal muscle wasting in tumour‐bearing mice

Brown

Lee

Rosa‐Caldwell

et al. 2018

J cachexia sarcopenia muscle

135

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“…Muscle glutamate metabolism is disturbed in many conditions, such as hypoxia and oxidative stress [ 21 ]. Aspartate (the anion of aspartic acid) has been shown to inhibit inflammation-induced muscle loss through regulating phosphorylation of Akt, AMPKα, and FOXO1 in a piglet model [ 22 ]. Our pathway analysis further highlights potential important roles of several amino acid metabolic pathways involving both glutamic acid and aspartic acid, such as the pathways of alanine, aspartate, and glutamate metabolism as well as arginine and proline metabolism, in muscle regulation.…”

Section: Discussionmentioning

confidence: 99%

A joint analysis of metabolomic profiles associated with muscle mass and strength in Caucasian women

Zhao

Shen

et al. 2018

Aging

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Both loss of muscle mass and strength are important sarcopenia-related traits. In this study, we investigated both specific and shared serum metabolites associated with these two traits in 136 Caucasian women using a liquid chromatography-mass spectrometry method. A joint analysis of multivariate traits was used to examine the associations of individual metabolites with muscle mass measured by the body mass index-adjusted appendicular lean mass (ALM/BMI) and muscle strength measured by hand grip strength (HGS). After adjusting for multiple testing, nine metabolites including two amino acids (aspartic acid and glutamic acid) and an amino acid derive (pipecolic acid), one peptide (phenylalanyl-threonine), one carbohydrate (methyl beta-D-glucopyranoside), and four lipids (12S-HETRE, arachidonic acid, 12S-HETE, and glycerophosphocholine) were significant in the joint analysis. Of them, the two amino acids (aspartic acid and glutamic acid) and two lipids (12S-HETRE and 12S-HETE) were associated with both ALM/BMI and HGS, and the other five were only associated with ALM/BMI. The pathway analysis showed the amino acid metabolism pathways (aspartic acid and glutamic acid) might play important roles in the regulation of muscle mass and strength. In conclusion, our study identified novel metabolites associated with sarcopenia-related traits, suggesting novel metabolic pathways for muscle regulation.

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“…These results suggest that one of the factors contributing to the decrease in muscle atrophy may be the concentration of amino acids in the plasma. These findings suggest that plasma BCAA, aspartate (28), and glutamate (29,30) levels may also reflect improvement of muscle atrophy in skeletal muscle, especially in slowtwitch muscle. In skeletal muscle, glutamate is biosynthesized from BCAAs, which may only reflect the muscle volume increase by BCAAs, but muscle atrophy is further improved when BCAAs are prescribed with glutamine, which is produced from glutamate and ammonia in the urea cycle (31).…”

Section: Discussionmentioning

confidence: 79%

Amino Acid Profile in 18 Patients with Rheumatic Diseases Treated with Glucocorticoids and BCAAs

Yoshikawa

Yamamoto

Kuribara-Souta

et al. 2021

J Nutr Sci Vitaminol

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The administration of glucocorticoids to patients with rheumatic diseases often results in glucocorticoid-induced myopathy. We previously found that administration of branched-chain amino acids (BCAA) to such patients improves the loss of skeletal muscle, however, their individual differences were often observed. The present study, therefore, aims to identify specific parameters associated with BCAA-induced increases in skeletal muscle mass. Eighteen patients with rheumatic diseases treated with prednisolone were randomly assigned to receive additional BCAAs for 12 wk. Serum biochemistry, plasma fibroblast growth factor (FGF) 19 and 21, and plasma and urinary amino acid concentrations were assessed. The relationship between these parameters and the cross-sectional area (CSA) of the biceps femoris (slow-twitch muscle) and rectus femoris (fast-twitch muscle) was assessed using computed tomography. BCAA supplementation increased serum levels of creatinine and albumin and decreased ammonia and urinary 3-methylhistidine levels. With or without BCAA supplementation, each plasma amino acid concentration decreased during the study period, but the decrease was lower in patients receiving BCAA. Interestingly, a positive correlation was observed between plasma isoleucine, aspartate, and glutamate concentrations and improvement in the biceps femoris muscle atrophy. Plasma amino acid concentrations in patients with rheumatic diseases treated with glucocorticoids decreased despite tapering the dose of glucocorticoids, with a smaller decrease in the BCAAtreated group. Plasma BCAA, aspartic acid, and glutamate concentrations correlated positively with the rate of improvement in biceps femoris muscle atrophy, suggesting that these amino acids are associated with the BCAA-induced increase in muscle mass.

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Aspartate inhibits LPS-induced MAFbx and MuRF1 expression in skeletal muscle in weaned pigs by regulating Akt, AMPKα and FOXO1

Cited by 10 publications

References 45 publications

Protein imbalance in the development of skeletal muscle wasting in tumour‐bearing mice

Protein imbalance in the development of skeletal muscle wasting in tumour‐bearing mice

A joint analysis of metabolomic profiles associated with muscle mass and strength in Caucasian women

Amino Acid Profile in 18 Patients with Rheumatic Diseases Treated with Glucocorticoids and BCAAs

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