Inhibitory effects of IL-6 on IGF-1 activity in skeletal myoblasts could be mediated by the activation of SOCS-3.
In elderly people, low and high levels of insulin-like growth factor 1 (IGF-1) and interleukin-6 (IL-6), respectively, are well documented and may contribute to reduced muscle mass and poor muscle function of ageing and suggesting a biological interactions between IGF-1 and IL-6. However, the dual effect of IGF-1/IL-6 on skeletal muscle differentiation and proliferation has not been fully investigated. We therefore hypothesised that IL-6 impairs the biological activity of IGF-1 in skeletal muscle through inhibiting its signalling pathways, ERK1/2 and Akt. Our aim was to examine the combined effects of these factors on models of muscle wasting, with objectives to examine skeletal muscle differentiation and proliferation using the murine C2 skeletal muscle cell line. Cells were cultured with DM, IGF-1 and IL-6 alone (control treatments), or co-cultured with IGF-1/IL-6. Co-incubation of C2 cells in IGF-1 plus IL-6 resulted in maximal cell death (22 ± 4%; P < 0.005) compared with control treatments (14 ± 2.9%). This was also confirmed by cyclin D1 expression levels in co-incubation treatments (7 ± 3.5%; P < 0.05) compared with control treatments (≈ 23%). The expression levels of myogenic-specific transcriptional factor mRNAs (myoD and myogenin) were also significantly (P < 0.005) reduced by 70% and 90%, respectively, under the co-incubation regimes, compared with control treatments. Signalling investigations showed significant phosphorylation reduction by 20%, (P < 0.05) of ERK1/2 and Akt in co-incubation treatments relative to either treatment alone. Expression studies for SOCS-3 (1.6-fold ± 0.08, P < 0.05) and IRS-1 (0.65-fold ± 0.13 P < 0.005) mRNAs showed significant elevation and reduction for both genes, respectively, in co-treatments relative to control treatments. These data may suggest that IL-6 exerts its inhibitory effects on IGF-1 signalling pathways (ERK1/2 and Akt) through blocking its receptor substrate IRS-1 by SOCS-3.
School of Healthcare Science, Institute for Biomedical Research into Human Movement and Health, Manchester Metropolitan University, Oxford Road, Manchester, M1 5GD, England, UK. n.al-shanti@mmu.ac.uk
Nasser
N
Al-Shanti
Claire E
CE
Stewart
D000818:Animals; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D051379:Mice; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins
D055504:Insulin Receptor Substrate Proteins; D015850:Interleukin-6; D018006:Myogenic Regulatory Factors; D012333:RNA, Messenger; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases