Direct effects of tumor necrosis factor alpha (TNF-alpha) on murine skeletal muscle cell lines. Bimodal effects on protein metabolism.
Incubation of murine C2C12 myotubes with tumour necrosis factor-alpha (TNF-alpha) leads to significant changes in protein content and turnover, suggesting that the cytokine exerts direct effects in skeletal muscle. The effects of the cytokine on protein content show a clear bimodal behaviour. At low concentrations (1 U/ml or less), TNF-alpha decreases both total and myofibrillar protein content, while at relatively high concentrations (100 U/ml or more), the effects are opposite and TNF-alpha increases the total and myofibrillar protein content in C2C12 myotubes. The mechanisms responsible for this latter, unexpected anabolic effect of the cytokine on muscle cells are related to a 40% increase in the rate of protein synthesis and to a significant decrease (14%) in the rate of protein degradation. At high concentrations, TNF-alpha decreased the expression of the mRNA of components of both the ATP- (ubiquitin, E2, C8) and Ca2+-dependent (m-calpain) proteolytic systems. The effects of TNF-alpha (10 U/ml or higher) on protein content of cultured murine myotubes (differentiated myogenic cells) were similar to those induced by insulin (1 or 5 microg/ml), but the effects of TNF-alpha and those of insulin were not additive. Experiments using inhibitors of the signalling pathways mediated by PI3K and MAP kinases (MAPKs) ERK1/2 and p38 suggest that insulin and TNF-alpha may share some intracellular signalling pathways involving MAPKs in the enhanced protein accretion observed in the muscle cell cultures.
Alvarez
B
B
Cancer Research Group, Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Diagonal 645, 08028-Barcelona, Spain.
Quinn
L S
LS
Busquets
S
S
López-Soriano
F J
FJ
Argilés
J M
JM
D000818:Animals; D002154:Calpain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007328:Insulin / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014176:Protein Biosynthesis; D011506:Proteins / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism
D007328:Insulin; D011506:Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D002154:Calpain