Abstract
Background: Leukemia inhibitory factor (LIF) is a pleiotropic cytokine, belonging to the interleukin-6 family of cytokines, that has been suggested to have positive effects on myogenesis following injury and to minimise dystrophic pathology in mdx mice. Previous reports have suggested that Lif mRNA is up-regulated in the limb and diaphragm muscles of mdx mice, in human cases of dystrophy and acutely following exercise. This study examined expression of Lif mRNA in the quadriceps muscles of mdx and wild-type mice that were either sedentary or allowed to exercise voluntarily for two weeks. Results: Exercise caused a decrease in Lif mRNA expression in wild-type muscle, but this was not the case in mdx muscle. Lif mRNA levels in sedentary mdx mice were similar to those in exercised wild type muscles, and in mdx mice there was no further decrease in levels following exercise. Similar down-regulation of Lif mRNA was observed in the tibialis anterior and diaphragm muscles of mdx mice at three and six weeks of age respectively, compared with wild-type controls. Transcripts for the LIF receptor (Lifr) were also down-regulated in these mdx muscles, suggesting LIF activity may be minimised in dystrophic muscle. However fluorescent immunohistochemical labeling of LIF did not correlate with transcript expression data, as LIF immunoreactivity could not be detected in wild-type muscle, where mRNA expression was high, but was present in dystrophic muscle where mRNA expression was low. This study also described the translocation of membrane proteins, including LIFR, to the nuclei of syncytial muscle cells during differentiation and fusion. In addition this study demonstrates that survival of donor myoblasts injected into dystrophic muscle was enhanced by co-administration of recombinant LIF.Conclusions: This study provides new evidence to support a role for LIF in normal muscle biology in response to exercise. Although expression levels of Lif transcript in mdx muscles were not consistent with previous studies, the detection of LIF protein in mdx muscle but not wild-type muscle supports a role for LIF in dystrophy. This study also provides evidence of the differential localisation of the LIFR, and the potential for anti-inflammatory actions of LIF that promote survival of transplanted myoblasts in dystrophic muscle.*corresponding author: Jason White, Muscular Dystrophy Research Group, Murdoch Childrens Research Institute; email: jasondw@unimelb.edu.au
Highlights
Leukemia inhibitory factor (LIF) is a pleiotropic cytokine belonging to the interleukin-6 (IL-6) family of cytokines, which all share the common receptor subunit gp130 [1]
Expression of Lif, LIF receptor (Lifr) and Il6st mRNA in the quadriceps of exercised and sedentary mdx and wild-type mice Histology of exercised mdx quadriceps muscles indicated that a greater degree of damage was achieved with voluntary exercise as numerous necrotic lesions with mononucleated cells and small myotubes were present compared to sedentary mdx (Figure 1)
Lif, Lifr and Il6st mRNA expression was analysed in quadriceps muscles from sedentary and exercised wild-type (C57BL10/ScSn) and mdx mice
Summary
Leukemia inhibitory factor (LIF) is a pleiotropic cytokine belonging to the interleukin-6 (IL-6) family of cytokines, which all share the common receptor subunit gp130 [1]. LIF is known to cause cellular effects on myoblasts by binding to a heterodimer of the gp130 and LIF receptor (LIFR) proteins [10] [11] [12] [13] which elicits downstream signaling via the common signaling mediators janus kinase (JAK), signal transducer and activator of transcription-3 (STAT3), phosphoinositide-3-kinase (PI3K) and mitogen activated protein kinase and extracellular-signal regulated kinase kinase (MEK) [14] Signaling via these mediators can lead to inhibition of myoblast apoptosis [6] and inhibition of myogenic differentiation [15] [16] [17]. Leukemia inhibitory factor (LIF) is a pleiotropic cytokine, belonging to the interleukin-6 family of cytokines, that has been suggested to have positive effects on myogenesis following injury and to minimise dystrophic pathology in mdx mice. This study examined expression of Lif mRNA in the quadriceps muscles of mdx and wild-type mice that were either sedentary or allowed to exercise voluntarily for two weeks
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