The Role of Leukemia Inhibitory Factor Receptor Signaling in Skeletal Muscle Growth, Injury and Disease

Hunt, Liam C.; White, Jason D.

doi:10.1007/978-3-319-27511-6_3

Cited by 25 publications

(14 citation statements)

References 72 publications

(83 reference statements)

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“…CNTFR-A is a cytokine receptor that is secreted from both neurons and skeletal muscle cells, but tissue-specific deletion studies revealed that these tissues play a non-redundant role in NMJ function [11,12]. CNTFR is released in a soluble functional form and attached to the extracellular surface of PMs by a glycosylphosphatidylinositol linkage where it functions as a co-receptor along with leukemia inhibitory factor receptor (LIFR) and gp130[13]. Ligands for this receptor complex include CNTF, cytokine like factor-1, and cardiotrophin-like cytokine factor 1 although studies suggest that the latter two are likely the ligands responsible for muscle terminal maintenance.…”

Section: Introductionmentioning

confidence: 99%

Muscle as a paracrine and endocrine organ

Giudice

Taylor

2017

Current Opinion in Pharmacology

253

186

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Skeletal muscle cells are highly abundant and metabolically active and are known to ‘communicate’ their energy demands to other organs through active secretion. Muscle-derived secretory proteins include a variety of cytokines and peptides collectively referred to as “myokines” that exert auto-, para- or endocrine effects. Analyses of the skeletal muscle secretome revealed that numerous myokines are secreted in response to contraction or strength training, and that these factors not only regulate energy demand but also contribute to the broad beneficial effects of exercise on cardiovascular, metabolic, and mental health. Herein we review recent studies on the myokines that regulate muscle function and those that mediate cross talk between skeletal muscle and other organs including adipose tissue, liver, pancreas, the cardiovascular system, brain, bones, and skin.

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Section: Introductionmentioning

confidence: 99%

Muscle as a paracrine and endocrine organ

Giudice

Taylor

2017

Current Opinion in Pharmacology

253

186

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“…Skeletal muscle serves as both a biological target and a source of the IL-6 family of cytokines. Two members of the IL-6 family, IL-6 and leukemia inhibitory factor (LIF), play recognized roles in both skeletal muscle hypertrophy and atrophy (26,45). Plasma elevation and muscle production of IL-6 and LIF occur under physiological conditions, involving repeated contractions during exercise and overload or muscle injury (10,18).…”

mentioning

confidence: 99%

Acute myotube protein synthesis regulation by IL-6-related cytokines

Gao

Durstine

Koh

et al. 2017

American Journal of Physiology-Cell Physiology

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IL-6 and leukemia inhibitory factor (LIF), members of the IL-6 family of cytokines, play recognized paradoxical roles in skeletal muscle mass regulation, being associated with both growth and atrophy. Overload or muscle contractions can induce a transient increase in muscle IL-6 and LIF expression, which has a regulatory role in muscle hypertrophy. However, the cellular mechanisms involved in this regulation have not been completely identified. The induction of mammalian target of rapamycin complex 1 (mTORC1)-dependent myofiber protein synthesis is an established regulator of muscle hypertrophy, but the involvement of the IL-6 family of cytokines in this process is poorly understood. Therefore, we investigated the acute effects of IL-6 and LIF administration on mTORC1 signaling and protein synthesis in C2C12 myotubes. The role of glycoprotein 130 (gp130) receptor and downstream signaling pathways, including phosphoinositide 3-kinase (PI3K)-Akt-mTORC1 and signal transducer and activator of transcription 3 (STAT3)-suppressor of cytokine signaling 3 (SOCS3), was investigated by administration of specific siRNA or pharmaceutical inhibitors. Acute administration of IL-6 and LIF induced protein synthesis, which was accompanied by STAT3 activation, Akt-mTORC1 activation, and increased SOCS3 expression. This induction of protein synthesis was blocked by both gp130 siRNA knockdown and Akt inhibition. Interestingly, STAT3 inhibition or Akt downstream mTORC1 signaling inhibition did not fully block the IL-6 or LIF induction of protein synthesis. SOCS3 siRNA knockdown increased basal protein synthesis and extended the duration of the protein synthesis induction by IL-6 and LIF. These results demonstrate that either IL-6 or LIF can activate gp130-Akt signaling axis, which induces protein synthesis via mTORC1-independent mechanisms in cultured myotubes. However, IL-6- or LIF-induced SOCS3 negatively regulates the activation of myotube protein synthesis.

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“…However, LIFR could not activate the STAT3 pathway, which suggested that LIFR did not function through the STAT3 pathway in HTR8/SVneo cells. LIFR is an important receptor of several members of interleukin 6 family, such as leukemia inhibitory factor (LIF), oncostatin M (OSM), cardiotrophin 1 (CT1) and ciliary neurotrophic factor (CNTF) (Plun-Favreau et al 2003, Hunt & White 2016. It mediates many signaling pathways in different cells and tissues, including JAK/STAT3, MAPK/ERK1/2, MAPK/p38 and PI3K/AKT (Schiemann et al 1995, Godoy-Tundidor et al 2005, Magni et al 2007.…”

Section: Discussionmentioning

confidence: 99%

LIFR increases the release of soluble endoglin via the upregulation of MMP14 expression in preeclampsia

Yao

Chang

et al. 2018

Reproduction

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Preeclampsia (PE) is a pregnancy-specific disorder that is the main cause of maternal and perinatal morbidity and mortality worldwide. Inadequate trophoblastic invasion and endothelial dysfunction in the placenta are considered the foundation of the pathogenesis of preeclampsia in which soluble endoglin (sENG) plays an antiangiogenic role in the development of PE. The leukemia inhibitory factor receptor (LIFR) has been widely studied and is highly involved in arterial injury and in the migration of cancer cells Here, we tested the hypothesis that LIFR may be correlated with preeclampsia through its regulation of the release of sENG. Our data showed that LIFR protein, the expression of which significantly decreased with the progression of pregnancy, was located in the syncytiotrophoblast and cytotrophoblast. The LIFR protein level was increased in pregnancies with preeclampsia compared with normotensive full-term pregnancies. After the overexpression of LIFR in HTR8/SVneo cells, the release of sENG as well as the migration and invasion were significantly enhanced. Moreover, we also observed that LIFR induced the expression of matrix metalloproteinase14 (MMP14) and that the knockdown or inhibition of MMP14 decreased the release of sENG, as well as increased the LIFR-induced migration and invasion of HTR8/SVneo cells. These studies demonstrated that LIFR promoted the release of sENG through MMP14 , which indicates that LIFR may be involved in the development of preeclampsia.

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The Role of Leukemia Inhibitory Factor Receptor Signaling in Skeletal Muscle Growth, Injury and Disease

Cited by 25 publications

References 72 publications

Muscle as a paracrine and endocrine organ

Muscle as a paracrine and endocrine organ

Acute myotube protein synthesis regulation by IL-6-related cytokines

LIFR increases the release of soluble endoglin via the upregulation of MMP14 expression in preeclampsia

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