Pro- and anti-apoptotic roles for IGF-I in TNF-alpha-induced apoptosis: a MAP kinase mediated mechanism.
OBJECTIVE
The concept of skeletal muscle homeostasis--often viewed as the net balance between two separate processes, namely protein degradation and protein synthesis--are not occurring independently of each other, but are finely co-ordinated by a web of intricate signalling networks.


METHODS
Using rodent muscle cell lines we have investigated TNF-alpha/IGF-I interactions, in an attempt to mimic and understand mechanisms underlying the wasting process.


CONCLUSIONS
When myoblast cells are incubated with TNF-alpha (10 ng ml(- 1)) maximal damage ( approximately 21% +/- 0.7 myoblast death, p < 0.05) was induced. Co-incubation of TNF-alpha (10 ng ml(- 1)) with IGF-I resulted in cell survival ( approximately 50% reduction in myoblast death, p < 0.05), however, myotube formation was not evident. In contrast, a novel role of IGF-I has been identified whereby co-incubation of muscle cells with IGF-I (1.5 ng ml(- 1)) and a non-apoptotic dose of TNF-alpha (1.25 ng ml(- 1); sufficient to block differentiation) unexpectedly were shown not to rescue a block on differentiation but to facilitate significant myoblast death (p < 0.05). Interestingly, pre-administration of PD98059, a MAPK signal-blocking agent followed by co-incubation of 1.25 ng ml(- 1) TNF-alpha and 1.5 ng ml(- 1) IGF-I, reduced death to baseline levels (p < 0.05). We show for the first time that IGF-I can be apoptotic in the absence of TNF-alpha-induced cell death.
Saini
Amarjit
A
Institute for Biomedical Research into Human Movement and Health, Manchester Metropolitan University, Cheshire, UK. a.saini@mmu.ac.uk
Al-Shanti
Nasser
N
Faulkner
Steve H
SH
Stewart
Claire E
CE
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003402:Creatine Kinase / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D015151:Immunoblotting; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis / Q000378:metabolism*; D032448:Myoblasts, Skeletal / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007334:Insulin-Like Growth Factor I; D020928:Mitogen-Activated Protein Kinases; D003402:Creatine Kinase