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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
Author(s) -
Girven Matthew,
Dugdale Hannah F.,
Owens Daniel J.,
Hughes David C.,
Stewart Claire E.,
Sharples Adam P.
Publication year - 2016
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.25380
Subject(s) - myogenesis , myogenin , glutamine , muscle atrophy , myocyte , glutamine synthetase , endocrinology , skeletal muscle , medicine , tumor necrosis factor alpha , biology , p38 mitogen activated protein kinases , c2c12 , atrophy , mapk/erk pathway , signal transduction , microbiology and biotechnology , biochemistry , amino acid
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.