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l-glutamine Improves Skeletal Muscle Cell Differentiation and Prevents Myotube Atrophy After Cytokine (TNF-α) Stress Via Reduced p38 MAPK Signal Transduction
Journal article   Open access   Peer reviewed

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

Matthew Girven, Hannah F Dugdale, Daniel J Owens, David C Hughes, Claire E Stewart and Adam P Sharples
Journal of cellular physiology, Vol.231(12), pp.2720-2732
12/2016
DOI: 10.1002/jcp.25380
PMID: 26991744
url
https://researchonline.ljmu.ac.uk/id/eprint/3305/1/J%20Cell%20Physiol%20for%20RG%20%26%20Symplectic%20final%20submitted%20version.pdfView
Open Access

Abstract

Tumour Necrosis Factor-Alpha (TNF-α) 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-α (20 ng · ml(-1) ) ± l-glutamine (20 mM). TNF-α 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-α 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-α. Importantly, 20 mM l-glutamine reduced p38 MAPK activity in TNF-α 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-α 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. J. Cell. Physiol. 9999: 231: 2720-2732, 2016. © 2016 Wiley Periodicals, Inc.
 Animals Atrophy Cell Differentiation - drug effects Cell Fusion Cell Shape - drug effects Cell Survival - drug effects Cell Survival - genetics Gene Expression Regulation - drug effects Glutamine - pharmacology MAP Kinase Signaling System - drug effects Mice Muscle Development - drug effects Muscle Fibers, Skeletal - drug effects Muscle Fibers, Skeletal - enzymology Muscle Fibers, Skeletal - pathology Myoblasts, Skeletal - pathology p38 Mitogen-Activated Protein Kinases - metabolism Phosphorylation - drug effects Stress, Physiological - drug effects Tumor Necrosis Factor-alpha - pharmacology

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