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An anti-inflammatory role for leukemia inhibitory factor receptor signaling in regenerating skeletal muscle

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Abstract

Skeletal muscle regeneration in pathology and following injury requires the coordinated actions of inflammatory cells and myogenic cells to remove damaged tissue and rebuild syncytial muscle cells, respectively. Following contusion injury to muscle, the cytokine leukemia inhibitor factor (LIF) is up-regulated and knockout of Lif negatively impacts on morphometric parameters of muscle regeneration. Although it was speculated that LIF regulates muscle regeneration through direct effects on myogenic cells, the inflammatory effects of LIF have not been examined in regenerating skeletal muscle. Therefore, the expression and function of LIF was examined using the antagonist MH35-BD during specific inflammatory and myogenic stages of notexin-induced muscle regeneration in mice. LIF protein and mRNA were up-regulated in two distinct phases following intramuscular injection of notexin into tibialis anterior muscles. The first phase of LIF up-regulation coincided with the increased expression of pro-inflammatory cytokines; the second phase coincided with myogenic differentiation and formation of new myotubes. Administration of the LIF receptor antagonist MH35-BD during the second phase of LIF up-regulation had no significant effects on transcript expression of genes required for myogenic differentiation or associated with inflammation; there were no significant differences in morphometric parameters of the regenerating muscle. Conversely, when MH35-BD was administered during the acute inflammatory phase, increased gene transcripts for the pro-inflammatory cytokines Tnf (Tumor necrosis factor), Il1b (Interleukin-1β) and Il6 (Interleukin-6) alongside an increase in the number of Ly6G positive neutrophils infiltrating the muscle were observed. This was followed by a reduction in Myog (Myogenin) mRNA, which is required for myogenic differentiation, and the subsequent number of myotubes formed was significantly decreased in MH35-BD-treated groups compared to sham. Thus, antagonism of the LIF receptor during the inflammatory phase of skeletal muscle regeneration appeared to induce an inflammatory response that inhibited subsequent myotube formation. We propose that the predominant role of LIF in skeletal muscle regeneration appears to be in regulating the inflammatory response rather than directly effecting myogenic cells.

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Acknowledgments

The authors acknowledge the contributions of Kitipong Uaesoontrachoon and Charles Pagel for providing oligonucleotide primer sequences for the genes Myod1 and Myog. Su Toulson should also be acknowledged for her contributions toward the sampling of mice and subsequent processing of those samples. This work was funded by the Muscular Dystrophy Association of Australia (MDA) and supported by the Victorian Government’s Operational Infrastructure Support Program.

Conflict of interest

The authors declare that no conflict of interest exists.

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Authors and Affiliations

  1. Faculty of Veterinary Science, University of Melbourne, Flemington road, Parkville, VIC, 3010, Australia

    Liam C. Hunt, Elizabeth M. Tudor & Jason D. White

  2. Muscular Dystrophy Research Group, Murdoch Childrens Research Institute, Royal Children’s Hospital, Flemington Road, Parkville, VIC, 3052, Australia

    Liam C. Hunt & Jason D. White

  3. Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Melbourne, VIC, 3052, Australia

    Aradhana Upadhyay & Jalal A. Jazayeri

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Correspondence to Jason D. White.

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418_2012_1018_MOESM1_ESM.jpg

Fig. S1 Quantitation of LIF in serum following intramuscular notexin injection by LIF ELISA. Data were analysed by Student’s t test comparing individual time points to uninjured (day 0), * represents P < 0.05, n = 5 (JPEG 502 kb)

418_2012_1018_MOESM2_ESM.jpg

Fig. S2 Relative mRNA levels for lymphocyte associated markers with notexin-induced regeneration following (a) MH35-BD administration at day 3 and (b) MH35-BD administration at day 0. Data were analysed by REST comparing MH35-BD to sham, * represents P < 0.05, n = 5 (JPEG 170 kb)

418_2012_1018_MOESM3_ESM.jpg

Fig. S3 Relative mRNA levels of Pcna with MH35-BD administration at day 0. Data were analysed by REST comparing MH35-BD to sham, * represents P < 0.05, n = 5 (JPEG 424 kb)

418_2012_1018_MOESM4_ESM.jpg

Fig. S4 A cross section of a tibialis anterior muscle 7 days after notexin injection immunofluorescently labeled for LIF without blocking peptide (−BP). A cross section of a tibialis anterior muscle 7 days after notein injection immunofluorescently labeled for LIF with the inclusion of the anti-LIF blocking peptide during incubation of the primary antibody (+BP) (JPEG 1476 kb)

418_2012_1018_MOESM5_ESM.jpg

Fig. S5 Relative mRNA levels of Lif with MH35-BD administration at a day 0 and b day 3. The same trend was observed for Lif expression as with Fig. 1B (JPEG 382 kb)

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Hunt, L.C., Upadhyay, A., Jazayeri, J.A. et al. An anti-inflammatory role for leukemia inhibitory factor receptor signaling in regenerating skeletal muscle. Histochem Cell Biol 139, 13–34 (2013). https://doi.org/10.1007/s00418-012-1018-0

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