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.

MATERIALS AND 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.

RESULTS AND CONCLUSION

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.