Interleukin-11 (IL11) inhibits myogenic differentiation of C2C12 cells through activation of extracellular signal-regulated kinase (ERK)

Cancer-associated cachexia (CAC) is a multifactorial wasting syndrome characterized by loss of skeletal muscle. Interleukin-11 (IL11), one of the IL6 family cytokines, is highly expressed in various types of cancer including cancers frequently associated with cachexia. However, the impact of IL11 on...

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Bibliographic Details
Published in:	Cellular signalling Vol. 101; p. 110509
Main Authors:	Drinkwater, Kimberly, Anderson, Blake, Seangmany, Nessa, Hampel, Dylan, Mody, Aaron, Shim, Minsub
Format:	Journal Article
Language:	English
Published:	England Elsevier Inc 01-01-2023
Subjects:	Animals Bromodeoxyuridine C2C12 Cachexia Cell Differentiation Extracellular Signal-Regulated MAP Kinases IL6 family cytokines Interleukin-11 Interleukin-11 - pharmacology Mice Muscle Development Myoblasts - drug effects Myoblasts - physiology Myogenesis Myogenin - genetics Myosin Heavy Chains - genetics Myosin Heavy Chains - metabolism Neoplasms IL11 CNTF IL6 family cytokines CAC Interleukin-11 cachexia LIF OSM MHC CT-1 IL27 Myogenesis C2C12 IL6 CLC ERK
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Summary:	Cancer-associated cachexia (CAC) is a multifactorial wasting syndrome characterized by loss of skeletal muscle. Interleukin-11 (IL11), one of the IL6 family cytokines, is highly expressed in various types of cancer including cancers frequently associated with cachexia. However, the impact of IL11 on muscle metabolism remains to be determined. Since one of the mechanisms of muscle wasting in cachexia is defective muscle regeneration due to impaired myogenic differentiation, we examined the effect of IL11 on the differentiation of C2C12 mouse myoblasts. Treatment of C2C12 cells with recombinant mouse IL11 resulted in decreased myotube formation. In addition, IL11 treatment reduced the protein and mRNA levels of myosin heavy chain (MHC), a marker of myogenic differentiation. Moreover, the levels of myogenic regulatory factors including myogenin and Mrf4 were significantly reduced by IL11 treatment. IL11 treatment increased the number of BrdU-positive cells and the level of phosphorylated retinoblastoma (Rb) protein, while the levels of p21Waf1 and p27Kip1 were reduced by IL11 treatment in differentiating C2C12 cells, suggesting that IL11 interferes with cell cycle exit during the early stages of myogenic differentiation. Consistent with this, IL11 treatment at the late stage of differentiation did not affect myotube formation and MHC expression. IL11 treatment resulted in an activation of ERK, STAT3, and AKT in differentiating C2C12 cells. However, only ERK inhibitors including PD98059 and U0126 were able to ameliorate the suppressive effect of IL11 on the expression of MHC and myogenin. Additionally, pretreatment with PD98059 and U0126 resulted in improved myotube formation and reduced BrdU staining in IL11-treated cells. Together, our results suggest that IL11 inhibits myogenic differentiation through delayed cell cycle exit in an ERK-dependent manner. To our knowledge, this study is the first to demonstrate an inhibitory role of IL11 in myogenic differentiation and identifies the previously unrecognized role of IL11 as a possible mediator of CAC. •IL11 suppressed the myogenic differentiation of C2C12 myoblasts.•IL11 resulted in delayed cell cycle exit in differentiating C2C12 cells.•ERK inhibition ameliorated the suppressive effect of IL11 on C2C12 myogenesis.•IL11 may play an important role in cancer-induced muscle wasting.
ISSN:	0898-6568 1873-3913
DOI:	10.1016/j.cellsig.2022.110509