IGF-I does not prevent myotube atrophy caused by proinflammatory cytokines despite activation of Akt/Foxo and GSK-3beta pathways and inhibition of atrogin-1 mRNA.
Myofibrillar protein loss occurring in catabolic situations is considered to be mediated by the release of proinflammatory cytokines and associated with a decrease in circulating and muscle levels of insulin-like growth factor I (IGF-I). In this paper, we investigated whether the C(2)C(12) myotube atrophy caused in vitro by TNF-alpha/IFN-gamma cytokines might be reversed by exogenous IGF-I. Our results showed that, despite the presence of TNF-alpha/IFN-gamma, IGF-I retained its full ability to induce the phosphorylation of Akt, Foxo3a, and GSK-3beta (respectively, 16-fold, 9-fold, and 2-fold) together with a decrease in atrogin-1 mRNA (-39%, P < 0.001). Although this ubiquitin ligase has been reported to accelerate the degradation of MyoD, a myogenic transcription factor driving the transcription of myosin heavy chain (MHC), IGF-I failed to blunt the reduction of MyoD and MHC caused by TNF-alpha/IFN-gamma. Moreover, IGF-I only very slightly attenuated the myotube atrophy induced by TNF-alpha/IFN-gamma (TNF-alpha/IFN-gamma 15.48 mum alone vs. TNF-alpha/IFN-gamma/IGF-I 16.97 mum, P < 0.001). In conclusion, our data show that IGF-I does not reverse the myotube atrophy induced by TNF-alpha/IFN-gamma despite the phosphorylation of Foxo and GSK-3beta and the downregulation of atrogin-1 mRNA. Our study suggests therefore that factors other than IGF-I decrease are responsible for the muscle atrophy caused by proinflammatory cytokines.
Dehoux
Mischaël
M
Division of Diabetology and Nutrition, Université catholique de Louvain, 54 avenue Hippocrate, B-1200 Brussels, Belgium.
Gobier
Catherine
C
Lause
Pascale
P
Bertrand
Luc
L
Ketelslegers
Jean-Marie
JM
Thissen
Jean-Paul
JP
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000009:adverse effects*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D018836:Inflammation Mediators / Q000009:adverse effects*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects; D009124:Muscle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009133:Muscular Atrophy / Q000209:etiology / Q000517:prevention & control*; D017570:MyoD Protein / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D018836:Inflammation Mediators; D009124:Muscle Proteins; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D014409:Tumor Necrosis Factor-alpha; D007334:Insulin-Like Growth Factor I; D007371:Interferon-gamma; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D018995:Myosin Heavy Chains