Interleukin-6/signal transducer and activator of transcription 3 (STAT3) pathway is essential for macrophage infiltration and myoblast proliferation during muscle regeneration
Open accessAbstract
Inflammation and microenvironment play a crucial role in muscle regeneration. IL (interleukin)-6, as a multifunctional cytokine is involved in the processes. However, the causative effect of IL-6 in muscle regeneration remains unclear. In a mouse model of cardiotoxin-induced muscle injury/regeneration, infiltrated monocytes/macrophages produce a high level of IL-6 started on 1 day (24 h) after injury. In IL-6 knock-out (−/−) mice, the muscle regeneration procedure was impaired along with decreased myogenic determination factor (MyoD) and myogenin mRNA level and increased interstitial fibrosis. The IL-6 −/− mice exhibited less macrophage infiltration, lower inflammatory cytokine (IL-1β, inducible NO synthase, Transforming growth factor (TGF)-β1, and IL-10) and chemokine (CCL2, CCL3, and CCL5) expression, and inhibited myoblast proliferation. In vitro , IL-6 deficiency or Signal Transducer and Activator of Transcription 3 (STAT3) knockdown in activated macrophage attenuated the expression of CCL2, CCL3, but not CCL5, which resulted in less macrophage migration. Moreover, inflammatory macrophages promoted myoblast proliferation in an IL-6-dependent manner. Finally, adoptive transfer IL-6 +/+ BM cells into IL-6 −/− mice rescued the impaired regeneration with improved MyoD and myogenin expression. Taken together, IL-6 expression and the activated STAT3 signaling pathway in monocytes/macrophages is a critical mediator of macrophage migration and myoblast proliferation during muscle regeneration. Background: Interleukin-6 (IL-6), as a multifunctional cytokine, was involved in the inflammation microenvironment of muscle regeneration. Results: In mice lacking IL-6, less macrophage recruitment and decreased myoblast proliferation impairs muscle regeneration. Conclusion: In monocytes/macrophages, activation of the IL-6/STAT3 pathway is critical to macrophage migration and myoblast proliferation during muscle regeneration. Significance: IL-6/STAT3 pathway is essential for muscle regeneration.
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Acute transient increases in inflammation play an important part in early regenerative processes of muscle adaptation, particularly in response to exercise.
“Acute transient increases in inflammation plays an important part in the early regenerative processes of muscle adaptation, particularly in response to exercise [54,55].”
From Potential Roles of n-3 PUFAs during Skeletal Muscle Growth and Regeneration (2018) · cites this paper as [55]
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Potential Roles of n-3 PUFAs during Skeletal Muscle Growth and Regeneration
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“Acute transient increases in inflammation plays an important part in the early regenerative processes of muscle adaptation, particularly in response to exercise [54,55].”
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“The effect of IL-6 inhibition on immune cell infiltration or proliferation has not been studied in hypertension models but our data are in agreement with the effects for IL-6 on tissue macrophages in different disease models (45).”
ResultFang, Z., Li, J., Yu, X., Zhang, D., Ren, G., Shi, B., Wang, C., Kosinska, A. D., Wang, S., Zhou, X., et al. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1501362 · Cited by 100 · see citing works
Glycine administration attenuates skeletal muscle wasting in a mouse model of cancer cachexia
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Profibrotic Activation of Human Macrophages in Systemic Sclerosis
Bhandari, R., Ball, M. S., Martyanov, V., Popovich, D., Schaafsma, E., Han, S., ElTanbouly, M. A., Orzechowski, N. M., Carns, M. A., Arroyo, E., et al. (2020) · Arthritis & Rheumatology · doi:10.1002/art.41243 · Cited by 90 · see citing works
“STAT3 signaling, which is induced by IL6, is a key mediator of macrophage activation in a variety of pathologic conditions (39,40), and is a regulator of macrophage migration (41).”
BackgroundLow-Frequency Electrical Stimulation Attenuates Muscle Atrophy in CKD—A Potential Treatment Strategy
Hu, L., Klein, J. D., Hassounah, F., Cai, H., Zhang, C., Xu, P., & Wang, X. H. (2014) · Journal of the American Society of Nephrology · doi:10.1681/asn.2014020144 · Cited by 90 · see citing works
The impact of interleukin-6 (IL-6) and mesenchymal stem cell-derived IL-6 on neurological conditions
Kerkis, I., da Silva, Á. R. D. B. P., & Araldi, R. P. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1400533 · Cited by 89 · see citing works
Exercise as an Anti-inflammatory Therapy for Cancer Cachexia: A Focus on Interleukin-6 Regulation.
Daou, H. (2019) · American Journal of Physiology. Regulatory Integrative and Comparative Physiology · doi:10.1152/ajpregu.00147.2019 · Cited by 74 · see citing works
Immunology Guides Skeletal Muscle Regeneration
Sass, F. A., Fuchs, M. A., Pumberger, M., Geißler, S., Duda, G. N., Perka, C., & Schmidt‐Bleek, K. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19030835 · Cited by 87 · see citing works
“They also stimulate myoblast proliferation in an IL-6 dependent manner [32].”
BackgroundThe Many Roles of Macrophages in Skeletal Muscle Injury and Repair
Wang, X., & Zhou, L. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.952249 · Cited by 92 · see citing works
“Pro-inflammatory macrophages also produce a high level of IL-6 (Zhang et al., 2013), TNF-α (Li, 2002), PGE2 (Ho et al., 2017), and A Disintegrin-Like and Metalloproteinase with Thrombospondin Type 1 Motif (ADAMTS1) (Du et al., 2017) that can stimulate satellite cell proliferation.”
BackgroundHenríquez‐Olguín, C., Altamirano, F. J., Valladares-Ide, D., Lopez, J. R., Allen, P. D., & Jaimovich, E. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.03.012 · Cited by 86 · see citing works
“IL-6 null mice showed an abnormal muscle repair, pointing to the importance of this cytokine in the regeneration process [58].”
Oyaizu, T., Enomoto, M., Yamamoto, N., Tsuji, K., Horie, M., Muneta, T., Sekiya, I., Okawa, A., & Yagishita, K. (2018) · Scientific Reports · doi:10.1038/s41598-018-19670-x · Cited by 85 · see citing works
Photobiomodulation and different macrophages phenotypes during muscle tissue repair
Souza, N. H. C., Mesquita‐Ferrari, R. A., Rodrigues, M. F. S. D., da Silva, D. D. F. T., Ribeiro, B. G., Alves, A. N., Garcia, M. P., Nunes, F. D., da Silva, E. M., França, C. M., et al. (2018) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.13757 · Cited by 84 · see citing works
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“Previous work suggests that IL-6 is produced by various resident cell types such as macrophages (Zhang et al. 2013), fibroblasts (Joe et al.”
BackgroundSkeletal Muscle Regeneration in Cardiotoxin-Induced Muscle Injury Models
Wang, Y., Lu, J., & Liu, Y. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113380 · Cited by 77 · see citing works
“Lee KP, 2015 Hindlimb muscle miR-431 Myoblast differentiation Up positive Improve [27] Storbeck CJ, 2013 Tibialis anterior SLK Myoblast differentiation Down Positive Improve [182] Lei, 2013 One leg of tibialis anterior MMP-13 Myoblast migration Down/Up Negative/Positive Impair/improve [183] Das, 2017 Tibialis anterior…”
BackgroundInfluentialCell Types Used for Cultured Meat Production and the Importance of Myokines
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“In monocytes and macrophages, IL-6 expression and activation of the STAT3 signaling pathway were key mediators of macrophage migration and myoblast proliferation during muscle regeneration [35].”
BackgroundStem Cell and Macrophage Roles in Skeletal Muscle Regenerative Medicine
Scala, P., Rehak, L., Giudice, V., Ciaglia, E., Puca, A. A., Selleri, C., Porta, G. D., & Maffulli, N. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221910867 · Cited by 76 · see citing works
“IL-6 −/− mice, the regenerative rate is lower because proteins related to myogenesis are poorly expressed and newly formed myofibers are smaller with interstitial fibrosis, and also because satellite cells and myoblasts show a lower proliferation and migration rate [89,90].”
BackgroundInfluentialBecker, M., Joseph, S. S., García‐Carrizo, F., Tom, R. Z., Opaleva, D., Serr, I., Tschöp, M. H., Schulz, T. J., Hofmann, S. M., & Daniel, C. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.08.010 · Cited by 73 · see citing works
“In particular, during muscle regeneration, IL6 secretion is induced in FAPs and MPs as a key source of this cytokine to promote SC proliferation and differentiation.(40,50) Since our mouse model only ablates the Il6 gene in myofibers, we conclude that this source is a key element in exercise-related muscle T cell phen…”
BackgroundLiu, X., Liu, Y., Zhao, L., Zeng, Z., Xiao, W., & Chen, P. (2016) · Cell Biology International · doi:10.1002/cbin.10705 · Cited by 73 · see citing works
“Inflammatory responses are integral components of the host reaction to muscle injury and play crucial roles in subsequent muscle regeneration (Zhang et al., 2013).”
BackgroundMetformin selectively dampens the acute inflammatory response through an AMPK-dependent mechanism
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The impact of senescence on muscle wasting in chronic kidney disease
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Palevski, D., Levin‐Kotler, L., Kain, D., Naftali‐Shani, N., Landa, N., Ben‐Mordechai, T., Konfino, T., Holbová, R., Molotski, N., Rosin‐Arbesfeld, R., et al. (2017) · Journal of the American Heart Association · doi:10.1161/jaha.116.004387 · Cited by 71 · see citing works
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“1 For example, Zhang et al 2 reported that paclitaxel significantly suppressed tubulointerstitial fibrosis by inhibiting TGF-β (transforming growth factor-beta)/Smad signaling in a rat model of unilateral ureteral obstruction (UUO).”
Liu, C., Chen, J., Chen, L., Huang, X., & Cheung, P. C. K. (2016) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.6b00932 · Cited by 68 · see citing works
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Diet‐induced obesity alters anabolic signalling in mice at the onset of skeletal muscle regeneration
Brown, L. A., Lee, D. E., Patton, J. F., Perry, R. A., Brown, J. L., Baum, J., Smith‐Blair, N., Greene, N. P., & Washington, T. A. (2015) · Acta Physiologica · doi:10.1111/apha.12537 · Cited by 65 · see citing works
“IL-6 plays a role in the recruitment and infiltration of phagocytes to the injured site of muscle at the onset of skeletal muscle regeneration (Zhang et al. 2013).”
BackgroundResultInfluentialMadaro, L., & Bouché, M. (2014) · BioMed Research International · doi:10.1155/2014/438675 · Cited by 66 · see citing works
“Much of the current information about the role of immune cell populations of the innate response in muscle repair comes from studies on healthy regenerating muscle [1, 18–20].”
BackgroundCX 3 CR1 deficiency delays acute skeletal muscle injury repair by impairing macrophage functions
Zhao, W., Lu, H., Wang, X., Ransohoff, R. M., & Zhou, L. (2015) · The FASEB Journal · doi:10.1096/fj.14-270090 · Cited by 65 · see citing works
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“(36) showing that IL-6 is critical in promoting macrophage infiltration in the muscle regeneration process, as well as the suggestion by Pei et al.”
BackgroundRole of interleukin-6 in regulation of immune responses to remodeling after myocardial infarction
Huang, M., Du, Y., Xiang, M., & Wang, J. (2014) · Heart Failure Reviews · doi:10.1007/s10741-014-9431-1 · Cited by 64 · see citing works
“IL-6 expression and the activated STAT3 signaling pathway in monocytes/macrophages is a critical mediator of macrophage migration and myoblast proliferation during muscle regeneration [78].”
BackgroundSarma, N. J., Tiriveedhi, V., Crippin, J. S., Chapman, W. C., & Mohanakumar, T. (2014) · Journal of Virology · doi:10.1128/jvi.03060-13 · Cited by 62 · see citing works
“Components of the IL-6R complex were shown to be essential for CCL2 expression (10).”
BackgroundRole of inflammasomes and cytokines in immune dysfunction of liver cirrhosis
Das, P. P., & Medhi, S. (2023) · Cytokine · doi:10.1016/j.cyto.2023.156347 · Cited by 63 · see citing works
MicroRNA-223-3p promotes skeletal muscle regeneration by regulating inflammation in mice
Cheng, N., Liu, C., Li, Y., Gao, S., Han, Y., Wang, X., Du, J., & Zhang, C. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.012263 · Cited by 60 · see citing works
“After acute muscle injury, the infiltrated macrophage is the main cellular source, and the increased IL-6 could stimulate the proliferation of MuSCs and promote the expression of chemokines CCL2 and CCL3 inmacrophages, which further enhances the infiltration of macrophages (8).”
BackgroundMethodResultInfluentialNrf2 augments skeletal muscle regeneration after ischaemia–reperfusion injury
Al‐Sawaf, O., Fragoulis, A., Rosen, C., Keimes, N., Liehn, E. A., Hölzle, F., Kan, Y. W., Pufe, T., Sönmez, T. T., & Wruck, C. J. (2014) · The Journal of Pathology · doi:10.1002/path.4418 · Cited by 59 · see citing works
“Recently, Zhang et al showed that interleukin-6 (IL-6) produced in macrophages is critical for MyoD activation and myoblast proliferation during muscle regeneration [21].”
BackgroundTuning Macrophage Phenotype to Mitigate Skeletal Muscle Fibrosis
Stepien, D. M., Hwang, C. D., Marini, S., Pagani, C. A., Sorkin, M., Visser, N. D., Huber, A. K., Edwards, N., Loder, S. J., Vasquez, K., et al. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.1900814 · Cited by 57 · see citing works
“Deletion of the proinflammatory cytokine IL-6 prevents macrophage recruitment to the site of injury with impairment of muscle regeneration (19).”
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“However, IL-6 is also essential for muscle regeneration (Zhang et al. 2013), because, it regulates myoblast proliferation and differentiation (Serrano et al. 2008).”
BackgroundBeiter, T., Hoene, M., Prenzler, F., Mooren, F. C., Steinacker, J. M., Weigert, C., Niess, A. M., & Munz, B. (2026) · PubMed · doi:10.22029/eir.2015.1695 · Cited by 56 · see citing works
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“IL-6 is not only a pro-inflammatory cytokine but also an important regulator of satellite cell proliferation during muscle injury repair (Serrano et al., 2008; Begue et al., 2013; Zhang et al., 2013).”
The Importance of Biophysical and Biochemical Stimuli in Dynamic Skeletal Muscle Models
Maleiner, B., Tomasch, J., Heher, P., Oliver Spadiut, A., Rünzler, D., & Fuchs, C. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.01130 · Cited by 56 · see citing works
“Studies in rodents demonstrated that production of IL-6 and leukemia inhibitory factor help to regenerate muscle tissue after injury by activating satellite cells (Barnard et al., 1994; Kurek et al., 1996, 1997; Zhang et al., 2013).”
BackgroundGorski, T., Mathes, S., & Krützfeldt, J. (2018) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12277 · Cited by 53 · see citing works
“display smaller myofibers than wild-type mice 15 days after CTX-induced muscle injury.(62) Furthermore, increases in”
BackgroundMechanisms of cooperative cell-cell interactions in skeletal muscle regeneration
Koike, H., Manabe, I., & Oishi, Y. (2022) · Inflammation and Regeneration · doi:10.1186/s41232-022-00234-6 · Cited by 55 · see citing works
“Indeed, systemic deletion of Il-6 was shown to prevent macrophage recruitment to the site of injury, and muscle regeneration was impaired, with decreased MYOD and myogenin expression in myoblasts [52].”
BackgroundRingleb, M., Javelle, F., Haunhorst, S., Bloch, W., Fennen, L., Baumgart, S., Drube, S., Reuken, P. A., Pletz, M. W., Wagner, H., et al. (2024) · The FASEB Journal · doi:10.1096/fj.202301619r · Cited by 68 · see citing works
“In the regenerating muscle, IL-6 is released by infiltrating neutrophils and macrophages, 112 by fibro-adipogenic progenitors, 113 and by satellite cells, 114,115 suggesting possible autocrine and paracrine functions of IL-6 in satellite cell-dependent myogenesis.”
BackgroundAge-associated inflammation and implications for skeletal muscle responses to exercise
Kunz, H. E., & Lanza, I. R. (2023) · Experimental Gerontology · doi:10.1016/j.exger.2023.112177 · Cited by 56 · see citing works
“This inflammatory environment appears crucial for recovery, as pre-clinical studies show that skeletal muscle regenerative capacity is impaired in the absence of TNFα, IL6, or IFN-γ (Peake et al., 2017; Serrano et al., 2008; Zhang et al., 2013; Collins and Grounds, 2001).”
BackgroundGitiaux, C., Latroche, C., Weiss‐Gayet, M., Rodero, M. P., Duffy, D., Bader‐Meunier, B., Glorion, C., Nusbaum, P., Bodemer, C., Mouchiroud, G., et al. (2017) · Arthritis & Rheumatology · doi:10.1002/art.40328 · Cited by 54 · see citing works
Careccia, G., Mangiavini, L., & Cirillo, F. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms25010512 · Cited by 59 · see citing works
“They remove muscle debris resulting from trauma and secrete cytokines, such as tumor necrosis factor α (TNF-α ) and Interleukin 6 (IL-6), which amplify the inflammatory status [58,59].”
BackgroundGomez‐Lopez, N., Olson, D. M., & Robertson, S. A. (2015) · Immunology and Cell Biology · doi:10.1038/icb.2015.63 · Cited by 51 · see citing works
Roest, A. S. V., Bersi, M. R., Clark, C. R., Zhang, Q., Sanders, L. H., Hatzopoulos, A. K., Force, T. L., Majka, S. M., Lal, H., & Merryman, W. D. (2019) · JCI Insight · doi:10.1172/jci.insight.131545 · Cited by 50 · see citing works
HDAC4 promotes Pax7‐dependent satellite cell activation and muscle regeneration
Choi, M., Ryu, S., Hao, R., Wang, B., Kapur, M., Fan, C., & Yao, T. (2014) · EMBO Reports · doi:10.15252/embr.201439195 · Cited by 49 · see citing works
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Freire, P. P., Fernández, G. J., Cury, S. S., de Moraes, D., Oliveira, J. S., de Oliveira, G., Dal‐Pai‐Silva, M., Reis, P. P., & Carvalho, R. F. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20081962 · Cited by 47 · see citing works
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Deficiency of IL-12p35 improves cardiac repair after myocardial infarction by promoting angiogenesis
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Immunometabolism of macrophages regulates skeletal muscle regeneration
Chen, Y.-F., Lee, C., Wu, H.-H., Lin, W., & Lee, O. K. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.948819 · Cited by 43 · see citing works
“In IL-6 deficient mice, the proliferation of MuSCs was abrogated (Serrano et al., 2008; Zhang et al., 2013), and IL-6 is also necessary for the complete differentiation of muscle cells.”
BackgroundAlves, A. N., Ribeiro, B. G., Fernandes, K. P. S., Souza, N. H. C., Rocha, L. A., Nunes, F. D., Bussadori, S. K., & Mesquita‐Ferrari, R. A. (2016) · Lasers in Medical Science · doi:10.1007/s10103-016-1908-9 · Cited by 43 · see citing works
“[26] found that monocytes/macrophages expressed the highest level of IL-6 mRNA, whereas muscle-resident cells (including myoblasts and fibroblasts) expressed very low levels.”
BackgroundThe multifaceted role of macrophages in homeostatic and injured skeletal muscle
Wang, X., & Zhou, L. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1274816 · Cited by 42 · see citing works
Regulatory role of microRNAs in virus-mediated inflammation
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“It has been demonstrated that reduction of IL-6 and IL-6R complex, along with STAT3 in mice results in downregulation of CCL2 [142].”
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“However, studies have shown that IL-6 is a hepatoprotective factor, which can predict alcoholic liver injury [46,47].”
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“IL-6 is a proinflammatory cytokine that exerts multiple effects in direct opposition to the anti-inflammatory cytokine IL-10, such as increasing inflammatory cell infiltration [22].”
BackgroundMicroRNA-570-3p regulates HuR and cytokine expression in airway epithelial cells.
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Glycerol-induced injury as a new model of muscle regeneration
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MicroRNA Regulated Macrophage Activation in Obesity
Li, C., Qu, L., Farragher, C., Vella, A., & Zhou, B. (2019) · Journal of Translational Internal Medicine · doi:10.2478/jtim-2019-0011 · Cited by 36 · see citing works
“[17] Interestingly, both M1 and M2 macrophages produce cytokine IL-6 that has both proinflammatory and anti-inflammatory functions[18] and is known to promote insulin secretion[19] or skeletal muscle tissue repair, depending on specific conditions.[20] M1 macrophages also release reactive molecules such as nitric oxid…”
Background
- Authors
- Zhang, C., Li, Y., Wu, Y., Wang, L., Wang, X., & Du, J.
- Affiliations
- Capital Medical University (CN)
- Corresponding author
- Du, Jie
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 288
- Issue
- 3
- Pages
- 1489-1499
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3548462
- OpenAlex
- W1969630360
- Cited by
- 279
- References
- 37
- Citations by year
- 2026: 16 · 2025: 15 · 2024: 21 · 2023: 17 · 2022: 20 · 2021: 23 · 2020: 21 · 2019: 20 · 2018: 27 · 2017: 25 · 2016: 22 · 2015: 19 · 2014: 20 · 2013: 12
- FWCI
- 6.55
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR060268)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- interleukin-6, STAT3 signaling, muscle regeneration, macrophage infiltration, myoblast proliferation, cardiotoxin-induced muscle injury, IL-6 knockout mice, macrophage migration, MyoD, myogenin, interstitial fibrosis, inflammatory cytokines, bone marrow-derived macrophages
- MeSH terms
- Animals, Cell Movement, Gene Expression Regulation, Macrophages, Regeneration, RNA, Messenger, Signal Transduction, Interleukin-6, MyoD Protein, Myogenin, Mice, Knockout, Muscle, Skeletal, Myoblasts, Cell Proliferation, STAT3 Transcription Factor, Mice, Cardiotoxins, Primary Cell Culture
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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