Abstract
BackgroundLeukemia inhibitory factor (LIF) is known to inhibit myogenic differentiation as well as to inhibit apoptosis and caspase-3 activation in non-differentiating myoblasts. In addition caspase-3 activity is required for myogenic differentiation. Therefore the aim of this study was to further investigate mechanisms of the differentiation suppressing effect of LIF in particular the possibility of a caspase-3 mediated inhibition of differentiation.ResultsLIF dependent inhibition of differentiation appeared to involve several mechanisms. Differentiating myoblasts that were exposed to LIF displayed increased transcripts for c-fos. Transcripts for the cell cycle inhibitor p21 as well as muscle regulatory factors myoD and myogenin were decreased with LIF exposure. However, LIF did not directly induce a proliferative effect under differentiation conditions, but did prevent the proportion of myoblasts that were proliferating from decreasing as differentiation proceeded. LIF stimulation decreased the percentage of cells positive for active caspase-3 occurring during differentiation. Both the effect of LIF inhibiting caspase-3 activation and differentiation appeared dependent on mitogen activated protein kinase and extracellular signal regulated kinase kinase (MEK) signalling. The role of LIF in myogenic differentiation was further refined to demonstrate that myoblasts are unlikely to secrete LIF endogenously.ConclusionsAltogether this study provides a more comprehensive view of the role of LIF in myogenic differentiation including LIF and receptor regulation in myoblasts and myotubes, mechanisms of inhibition of differentiation and the link between caspase-3 activation, apoptosis and myogenic differentiation.
Highlights
Leukemia inhibitory factor (LIF) is known to inhibit myogenic differentiation as well as to inhibit apoptosis and caspase-3 activation in non-differentiating myoblasts
Exogenous LIF delays myoblast differentiation and myotube formation A visual comparison of cultures incubated with 10 ng/mL LIF compared to untreated controls showed that 24 hours after differentiation was induced there appeared to be qualitatively less myotubes present in the LIFtreated compared to control cultures (Figure 1A)
Creatine kinase (CK) enzymatic activity increases over time as myoblasts differentiate and persists in fused myotubes [16]
Summary
Leukemia inhibitory factor (LIF) is known to inhibit myogenic differentiation as well as to inhibit apoptosis and caspase-3 activation in non-differentiating myoblasts. Proliferating satellite cells, termed myoblasts, subsequently differentiate and fuse to create myotubes which can mature into functional myofibers. These mono-nucleated muscle progenitor cells differentiation associated apoptotic signalling may contribute positively to myogenic differentiation, it may negatively lead to erroneous cell death [9]. Various proteins including growth factors and cytokines can regulate myogenic differentiation. One such cytokine, which shows increased expression in injured muscle undergoing myogenesis, is leukemia inhibitory factor (LIF) [10]
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