Leukemia inhibitory factor and interleukin-6 are produced by diseased and regenerating skeletal muscle

Abstract

The process of skeletal muscle regeneration following injury or disease involves locally produced growth factors which control cellular proliferation and differentiation. Leukemia inhibitory factor (LIF) and interleukin‐6 (IL‐6) have previously been shown to promote the proliferation of myoblasts in vitro, and thus may be involved in muscle regeneration. In the present investigation, the in vivo expression of these two myogenic growth factors was examined in regenerating muscle after a crush injury of wild‐type mice, and in diseased skeletal muscle and diaphragm of the mdx mouse. Using reverse transcription polymerase chain reaction we have demonstrated that while normal muscle rarely expresses mRNA for these two molecules, there is significant up‐regulation following injury, coinciding with the active period of muscle regeneration. This suggests these molecules act as locally produced trauma factors. This observation is reinforced in mdx mouse muscle, which is undergoing a cycle of degeneration and regeneration, and expresses both LIF and IL‐6. Using in situ hybridization, we have localized mRNA for LIF expression in the mdx diaphragm, suggesting that local production of these molecules by regenerating muscle itself, as well as by other cells in muscle, plays an important role in muscle regeneration. © 1996 John Wiley & Sons, Inc.

IL-6 signaling blockade increases inflammation but does not affect muscle function in the mdx mouse

“…Knock-out models of IL-6 have shown that it is necessary for proper muscle hypertrophy, activation of satellite cells, and regulation of extracellular matrix remodeling [38,39]. Thus the IL-6/muscle interaction is complex but chronic high levels of IL-6, as occurs in the mdx mouse, is likely detrimental to muscle [24]. …”

“…Indeed, transgenic mice overexpressing IL-6 suffer from severe muscle atrophy which can be ameliorated by blockade of IL-6 with IL-6r antibody [22]. Likewise, in the mdx mouse IL-6 muscle levels are dramatically elevated, while in age matched wild-type IL-6 is negligible; indeed, it’s barely detectable via western blot in wild-type mice [24]. Interestingly, muscle of wild-type mice, when injured, expresses IL-6 at a similar level to mdx mice, but control animal IL-6 levels quickly return to baseline.…”

Protective effects of leukemia inhibitory factor against oxidative stress during high glucose-induced apoptosis in podocytes

“…LIF is a pleiotropic cytokine belonging to the IL-6 family of cytokines (Gearing et al 1987), which is expressed in multiple tissues and involved in many biological processes. In the highly inflammatory, oxidative and apoptotic milieu of regenerating and dystrophic muscle (Sandri and Carraro 1999;Tidball 2005), levels of LIF are up-regulated (Kurek et al 1996). LIF may play a role as a trauma factor preventing myoblast cell death.…”

Postnatal profiles of myogenic regulatory factors and the receptors of TGF-β2, LIF and IGF-I in the gastrocnemius and rectus femoris muscles of dy mouse

“…Therefore, TGF-β, LIF and IGF-I have crucial roles in muscle regeneration in vivo following damage. Except for the diaphragm, the muscles of the mdx mouse were suggested to manifest marked enhancements of LIF, IL-6 [21] and bFGF in the cytosol [1,17]. Additionally, in the mdx mouse, satellite cells were reported to have a greater sensitivity to bFGF compared to control satellite cells [6].…”

“…For example, an in situ hybridization analysis by Bhagwati et al [3] revealed that, in the muscles of mdx mice, the expression of MyoD, which plays a crucial role in the proliferation of satellite cells [30], is up-regulated in the satellite cells and in the cytosol of immature fibers. The muscles, except for the diaphragm, of mdx mice are suggested to manifest conspicuous enhancements of leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) [21], and basic fibroblast growth factor (bFGF) and FGF receptor 2 in the cytosol [1,17]. Moreover, it has been shown that bFGF and myogenin are colocalized in the actively regenerating area in the muscles of mdx mice [9].…”