L-glutamine Improves Skeletal Muscle Cell Differentiation and Prevents Myotube Atrophy After Cytokine (TNF-alpha) Stress Via Reduced p38 MAPK Signal Transduction

Girven Matthew; Dugdale Hannah F.; Owens Daniel J.Hughes David C.Stewart Claire E.Sharples Adam P.

摘要

Tumour Necrosis Factor-Alpha (TNF-alpha) is chronically elevated in conditions where skeletal muscle loss occurs. As L-glutamine can dampen the effects of inflamed environments, we investigated the role of L-glutamine in both differentiating C2C12 myoblasts and existing myotubes in the absence/presence of TNF-alpha (20 ng.ml(-1)) +/- L-glutamine (20 mM). TNF-alpha reduced the proportion of cells in G1 phase, as well as biochemical (CK activity) and morphological differentiation (myotube number), with corresponding reductions in transcript expression of: Myogenin, Igf-I, and Igfbp5. Furthermore, when administered to mature myotubes, TNF-alpha induced myotube loss and atrophy underpinned by reductions in Myogenin, Igf-I, Igfbp2, and glutamine synthetase and parallel increases in Fox03, Cfos, p53, and Bid gene expression. Investigation of signaling activity suggested that Akt and ERK1/2 were unchanged, JNK increased (non-significantly) whereas P38 MAPK substantially and significantly increased in both myoblasts and myotubes in the presence of TNF-alpha. Importantly, 20mM L-glutamine reduced p38 MAPK activity in TNF-alpha conditions back to control levels, with a corresponding rescue of myoblast differentiation and a reversal of atrophy in myotubes. L-glutamine resulted in upregulation of genes associated with growth and survival including; Myogenin, Igf-Ir, Myhc2 & 7, Tnfsfr1b, Adra1d, and restored atrophic gene expression of Fox03 back to baseline in TNF-alpha conditions. In conclusion, L-glutamine supplementation rescued suppressed muscle cell differentiation and prevented myotube atrophy in an inflamed environment via regulation of p38 MAPK. L-glutamine administration could represent an important therapeutic strategy for reducing muscle loss in catabolic diseases and inflamed ageing. (C) 2016 Wiley Periodicals, Inc.

机译：肿瘤坏死因子-α(tnf)长期过高在骨骼的条件肌肉损失发生。发炎的环境的影响,我们研究了谷酰胺在分化的作用C2C12成肌细胞和现有肌管没有/ tnf的存在(20 ng.ml (1) + / -谷酰胺(20毫米)。在G1期细胞的比例,以及生化(CK活性)和形态分化(肌管数)相应的减少记录表达式: Myogenin、Igf-I Igfbp5。当管理成熟的肌管,tnf诱导肌管损失和萎缩支撑减少Myogenin、Igf-I Igfbp2,谷氨酰胺合成酶和并行的增加Fox03,首席财务官,p53基因表达。调查显示活动建议一种蛋白激酶和ERK1/2不变,物增加(与)而P38 MAPK显著和显著增加成肌细胞和肌管的存在tnf。回到tnf p38 MAPK活动条件控制水平,与相应的救助成肌细胞分化和逆转在肌小管萎缩。upregulation与增长,相关的基因包括生存;Tnfsfr1b Adra1d,恢复萎缩性基因在tnf的表达Fox03回到基线条件。补充了肌细胞抑制分化和预防肌小管萎缩通过调节p38的发炎的环境MAPK。一个重要的治疗策略,减少肌肉分解代谢的疾病和炎症老化。

L-glutamine Improves Skeletal Muscle Cell Differentiation and Prevents Myotube Atrophy After Cytokine (TNF-alpha) Stress Via Reduced p38 MAPK Signal Transduction

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