IL-1beta impairs insulin-like growth factor i-induced differentiation and downstream activation signals of the insulin-like growth factor i receptor in myoblasts.
Proinflammatory cytokines are elevated in disorders characterized by muscle wasting and weakness, such as inflammatory myopathies and AIDS wasting. We recently demonstrated that TNF-alpha impairs the ability of insulin-like growth factor (IGF)-I to promote protein synthesis in muscle precursor cells. In this study we extend these findings by showing that low concentrations of IL-1beta impair IGF-I-dependent differentiation of myoblasts, as assessed by expression of the muscle specific protein, myosin heavy chain. In the absence of exogenous IGF-I, IL-1beta (1 ng/ml) did not impair muscle cell development. However, in the presence of IGF-I, 100-fold lower concentrations of IL-1beta (0.01 ng/ml) significantly suppressed myoblast differentiation, protein synthesis, and myogenin expression. Increasing IL-1beta to 1 ng/ml completely blocked the anabolic actions of IGF-I in murine C(2)C(12) myoblasts. Similarly, IL-1beta inhibited IGF-I-stimulated protein synthesis in primary porcine myoblasts. IL-1beta impaired the actions of IGF-I at a point distal to the IGF receptor, and this was not due to IL-1beta-induced cell death. Instead, IL-1beta inhibited the ability of IGF-I to phosphorylate tyrosine residues on both of its downstream docking proteins, insulin receptor substrate 1 and insulin receptor substrate 2. These data establish that physiological concentrations of IL-1beta block the ability of IGF-I to promote protein synthesis, leading to reduced expression of the myogenic transcription factor, myogenin, and the subsequent development of more mature differentiated cells that express myosin heavy chain. Collectively, the results are consistent with the notion that very low concentrations of IL-1beta significantly impair myogenesis, but they are unable to do so in the absence of the growth factor IGF-I.
Broussard
Suzanne R
SR
Laboratories of Immunophysiology,207 Edward R. Madigan Laboratory, University of Illinois at Urbana-Champaign, 1201 West Gregory Drive, Urbana, IL 61801, USA. broussar@uiuc.edu
McCusker
Robert H
RH
Novakofski
Jan E
JE
Strle
Klemen
K
Shen
Wen Hong
WH
Johnson
Rodney W
RW
Dantzer
Robert
R
Kelley
Keith W
KW
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D007375:Interleukin-1 / Q000494:pharmacology*; D051379:Mice; D024510:Muscle Development / Q000187:drug effects*; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects*; D018008:Myogenin / Q000096:biosynthesis; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D013552:Swine
D007375:Interleukin-1; C503801:Myog protein, mouse; D018008:Myogenin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1