The DOI matches its Crossref record; 54 of the 57 references it cites were found in a registry or an index.
Interleukin-6 Is an Essential Regulator of Satellite Cell-Mediated Skeletal Muscle Hypertrophy
Open accessAbstract
Skeletal muscles adapt to increasing workload by augmenting their fiber size, through mechanisms that are poorly understood. This study identifies the cytokine interleukin-6 (IL-6) as an essential regulator of satellite cell (muscle stem cell)-mediated hypertrophic muscle growth. IL-6 is locally and transiently produced by growing myofibers and associated satellite cells, and genetic loss of IL-6 blunted muscle hypertrophy in vivo. IL-6 deficiency abrogated satellite cell proliferation and myonuclear accretion in the preexisting myofiber by impairing STAT3 activation and expression of its target gene cyclin D1. The growth defect was indeed muscle cell intrinsic, since IL-6 loss also affected satellite cell behavior in vitro, in a STAT3-dependent manner. Myotube-produced IL-6 further stimulated cell proliferation in a paracrine fashion. These findings unveil a role for IL-6 in hypertrophic muscle growth and provide mechanistic evidence for the contribution of satellite cells to this process.
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In the citing paper
“For instance, the pro-inflammatory cytokine IL-6 mediates lipid oxidation [7], induces the production of anti-inflammatory interleukins during exercise (e.g. IL-10 and IL-1ra) [8] and stimulates muscle growth [9].”
In the citing paper
“In vitro, IL-6 bears anabolic effects by regulating satellite cells’ function and enhancing glucose metabolism; furthermore, a loss of IL-6 signaling in myoblasts results in a reduced proliferation and migration [49,50].”
From Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting (2023) · cites this paper as [50]
In the citing paper
“Elimination of these cytokines in vivo has been shown to diminish muscle repair [118].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [118]
In the citing paper
“Briefly, a number of studies have shown that the chemokines and cytokines (TNF-α, IL-1β, IL-6) produced by initially infiltrating M1 macrophages are chemoattractant and mitogenic for muscle progenitor cells, including Pax7+ satellite cells [115–119].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [118]
In the citing paper
“Although the myokine IL-6 is mostly recognized for its regulatory effects in lipid and glucose metabolism, IL-6 also plays important roles in myogenesis.”
From Muscle–Organ Crosstalk: The Emerging Roles of Myokines (2020) · cites this paper as [49]
In the citing paper
“Genetic loss of IL-6 impaired muscle hypertrophy in vivo, whereas myotube-produced IL-6 stimulated muscle cell proliferation in a paracrine fashion (49).”
From Muscle–Organ Crosstalk: The Emerging Roles of Myokines (2020) · cites this paper as [49]
In the citing paper
“Although being considered pro-inflammatory, TNF-α and IL-6 also appear to play important role in the early stages of muscle regeneration following injury by enhancing myoblast proliferation and inhibiting differentiation [73,74,75].”
From Potential Roles of n-3 PUFAs during Skeletal Muscle Growth and Regeneration (2018) · cites this paper as [73]
In the citing paper
“This inhibition involves the down regulation of the MRFs, MyoD and Myogenin [73,74,75], with TNF-α receptor double knock out mice [74] and with IL-6 non-specific knock out mice [73] shown to present impaired myogenic differentiation and hypertrophy when compared to wild type mice during functional overloading.”
From Potential Roles of n-3 PUFAs during Skeletal Muscle Growth and Regeneration (2018) · cites this paper as [73]
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“Some possible areas in which DPP-IV could be involved are the modulation of blood flow via vasoactive NPY (Evanson et al. 2011) and satellite cell proliferation through interactions with SDF-1 (Kucia et al. 2004) and IL-6 (Hoffmann et al. 1993; Serrano et al. 2008; Toth et al. 2011).”
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“While some studies specify the presence and concentration of myokines at tissue level, a major proportion of the experiments rely on the plasma myokine levels, which reflect systemic levels [18].”
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“In particular, IL-6 is thought to stimulate muscle satellite cells and play important roles in muscle hypertrophy [12].”
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“Temporary increases in IL-6 induced by physical activity promote nutrient mobilization and muscle growth [29–31].”
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Nagahisa, H., Okabe, K., Iuchi, Y., Fujii, J., & Miyata, H. (2015) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/9345970 · Cited by 12
“IL-6 is a satellite cell activator through the JAK/STAT3 signaling pathway (Janus kinase/signal transducer and activators of transcription 3) [15, 16], and it has been demonstrated to be a regulatory factor essential for skeletal muscle hypertrophy in a compensatory overload experiment using IL-6 KO mice [17].”
BackgroundMartins, M. S., Farinha, J. B., Benetti, C. B., Courtes, A. A., Duarte, T., da Silva, J. C. N., Duarte, M. M. M. F., Soares, F. A. A., & dos Santos, D. L. (2015) · PubMed · doi:10.3305/nh.2015.32.2.8696 · Cited by 10
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Overload-mediated skeletal muscle hypertrophy is not impaired by loss of myofiber STAT3
Pérez‐Schindler, J., Esparza, M. C., McKendry, J., Breen, L., Philp, A., & Schenk, S. (2017) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00100.2017 · Cited by 10
“Contrasting this, however, IL-6 knockout mice exhibit normal skeletal muscle fiber CSA under basal conditions and, though not fully understood, adaptive growth appears to be abnormal compared with wild-type mice (15, 22).”
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Cappelletti, C., Galbardi, B., Bruttini, M., Salerno, F., Canioni, E., Pasanisi, M. B., Rodolico, C., Brizzi, T., Mora, M., Renieri, A., et al. (2019) · The FASEB Journal · doi:10.1096/fj.201801577rr · Cited by 10
“In the last decade, several findings showed that muscle-derived IL-6 might potentially modulate proliferation and differentiation of satellite cells, driving the myogenic program (26, 28, 29).”
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“…such as skeletal muscle for IL-6: release of IL-6 increased from skeletal muscle after prolonged exercise is known to be associated with stimulation of hypertrophic muscle growth and myogenesis of muscle stem cells in human ASCs (Serrano et al., 2008; Muñoz-Cánoves et al., 2013; Seo et al., 2018).”
BackgroundTargeted therapy of tumour microenvironment by gold nanoparticles as a new therapeutic approach
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“120 While slightly elevated IL-6 levels appear to benefit muscle tissue, chronically elevated levels lead to muscle atrophy during aging and disease.”
Resistance Exercise in a Hot Environment Alters Serum Markers in Untrained Males
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Caffeine Augments the Lactate and Interleukin-6 Response to Moderate-Intensity Exercise
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“Copyright © 2023 by the American College of Sports Medicine skeletal muscle hypertrophy and attenuation of sarcopenia (12), and improving glucose tolerance and insulin sensitivity (13,14).”
BackgroundRepurposing Approved Drugs for Sarcopenia Based on Transcriptomics Data in Humans
Liang, S., Liu, D., Xiao, Z., Greenbaum, J., Shen, H., Xiao, H., & Deng, H. (2023) · Pharmaceuticals · doi:10.3390/ph16040607 · Cited by 9
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“Serrano et al reported that IL-6 is an essential regulator of satellite cells.(36) Moreover,”
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“IL-6 is also known to play a role in glucose homeostasis regulation during exercise and contribute to hypertrophic muscle growth through satellite cells (Serrano et al., 2008).”
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“migration to fill in damaged areas [33,64,66].”
BackgroundIsoinertial and Isokinetic Sprints: Muscle Signalling
Fuentes, T., Ponce‐González, J. G., Morales‐Álamo, D., de Torres-Peralta, R. S., Santana, A., de Pablos-Velasco, P. L., Olmedillas, H., Guadalupe‐Grau, A., Rodríguez‐García, L., Serrano, J. A., et al. (2012) · International Journal of Sports Medicine · doi:10.1055/s-0032-1312583 · Cited by 9
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“Besides the direct effect of IL-6 on SCs, changes in IL-6 levels may also be involved in the remodeling of the niche, as IL-6 KO mice show lower levels of FN (Serrano et al. 2008).”
BackgroundDevelopment, repair, and regeneration of the limb musculoskeletal system
Song, J. Y., Pineault, K. M., & Wellik, D. M. (2019) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2018.12.011 · Cited by 9
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Advancements in two-dimensional nanomaterials for regenerative medicine in skeletal muscle repair
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“These factors are involved in exercise-induced metabolic adaptations, such as glucose regulation [19], lipid homeostasis [20], and increases in muscle mass and vascularization [21].”
Lu, X., Sharko, O. L., Shmanai, V. V., Shchepinov, M. S., & Markworth, J. F. (2026) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2026.02.037 · Cited by 9
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“However, myokine deficiency causes STAT3 downregulation, and cannot activate the cyclin D1 gene [65].”
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“On the other hand, it has been noted that IL-6 is an essential regulator of skeletal muscle hypertrophy due to satellite cell activation [92].”
BackgroundIn vitro effects of exercise on the heart
Youtz, D. J., Isfort, M. C., Eichenseer, C. M., Nelin, T. D., & Wold, L. E. (2014) · Life Sciences · doi:10.1016/j.lfs.2014.08.015 · Cited by 8
“Myotubes/Skeletal Muscle—Unlike cardiomyocyte in vitro studies, there is an abundance of information regarding the underlying mechanisms of in vitro skeletal muscle hypertrophy (Fujita et al., 2007, Nedachi et al., 2008, Nikolić et al., 2012, Serrano et al., 2008).”
BackgroundFunction of Membrane-Associated Proteoglycans in the Regulation of Satellite Cell Growth
Song, Y. Y. (2016) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-27511-6_4 · Cited by 7
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“IL-6 subsequently acts to promote the repair process because mice lacking IL-6 fail to undergo regenerative myogenesis (7).”
BackgroundHuman skeletal muscle ageing atlasPreprint
Kedlian, V. R., Wang, Y., Liu, T., Chen, X., Bolt, L., Shen, Z., Fasouli, E. S., Prigmore, E., Kleshchevnikov, V., Li, T., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.05.24.493094 · Cited by 8
Trinh, B., Peletier, M., Simonsen, C., Plomgaard, P., Karstoft, K., Pedersen, B. K., van Hall, G., & Ellingsgaard, H. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac239 · Cited by 7
The pathogenesis of immune-mediated necrotizing myopathy: Progress and therapeutic implications
Yang, M., Bi, Z., Li, Z., Zhan, J., Gao, H., Zhang, Q., Tang, Z., & Bu, B. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.118525 · Cited by 7
Ruan, T., Harney, D., Koay, Y. C., Loo, L., Larance, M., & Caron, L. (2022) · Cells · doi:10.3390/cells11060963 · Cited by 7
“IL6 plays a central role in skeletal muscle regeneration and hypertrophy by regulating satellite cell differentiation [62].”
BackgroundIdentification of C-C motif chemokine ligand 5 as a heat-dependent myokine
Murata, K., Ishiuchi, Y., & Nedachi, T. (2023) · Endocrine Journal · doi:10.1507/endocrj.ej22-0611 · Cited by 7
Akieda‐Asai, S., Ma, H., Han, W., Nagata, J., Yamaguchi, F., & Date, Y. (2024) · Scientific Reports · doi:10.1038/s41598-024-57727-2 · Cited by 7
“In skeletal muscle, IL-6 is produced not only by infiltrating macrophages but also by myocytes and satellite cells 37,38 .”
BackgroundDiagnostic and predictive abilities of myokines in patients with heart failure
Berezin, O. O., Berezina, T. A., Hoppe, U. C., Lichtenauer, M., & Berezin, A. Е. (2024) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2023.12.021 · Cited by 8
Health benefits of physical activity: What role does skeletal muscle-organ crosstalk play?
Powers, S. K., Goldstein, E. R., Lategan-Potgieter, R., Schrager, M. A., Skelton, M., & Demirel, H. A. (2025) · Sports Medicine and Health Science · doi:10.1016/j.smhs.2025.02.010 · Cited by 7
“149 ,150 Further, the myokines IL-7 and IL-15 both have anabolic properties in skeletal muscle fi bers.”
Lewis, F., Cottle, B. J., Shone, V., Marazzi, G., Sassoon, D. A., Tseng, C. C. S., Dankers, P. Y. W., Chamuleau, S. A. J., Nadal‐Ginard, B., & Ellison, G. M. (2017) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2017.08.002 · Cited by 7
Chi, C.-P., Hou, C.-W., Wu, Y.-Y., Wang, T., & Yu, S.-H. (2020) · General Physiology and Biophysics · doi:10.4149/gpb_2019047 · Cited by 8
“IL-6 release appears to be related to metabolic states (Pedersen et al. 2007) and the magnitude of IL-6 release maybe associated with the resulting degree of adaptation in muscle (Serrano et al. 2008).”
BackgroundInfluentialIL-6 production of C2C12 cells is enhanced in the presence of macrophages and pravastatin
Cseri, K., Szentesi, P., & Csernoch, L. J. (2021) · General Physiology and Biophysics · doi:10.4149/gpb_2021017 · Cited by 7
Ribieras, A. J., Ortiz, Y. Y., Li, Y., Le, N., Huerta, C. T., Voza, F. A., Shao, H., Vázquez-Padrón, R. I., Liu, Z., & Velazquez, O. C. (2023) · Cardiovascular Therapeutics · doi:10.1155/2023/6679390 · Cited by 7
“IL-6 is an essential regulator of skeletal muscle hypertrophy in response to muscle lengthening [49, 50] and promotes satellite cell proliferation via autocrine and paracrine signaling via janus kinase (JAK)/signal transducer and activator of transcription (STAT).”
BackgroundA necrotic stimulus is required to maximize matrix-mediated myogenesis in mice
Kuraitis, D., Berardinelli, M. G., Suuronen, E. J., & Musarò, A. (2013) · Disease Models & Mechanisms · doi:10.1242/dmm.011072 · Cited by 7
“IL-6 is produced by SCs and growing myofibers and its absence reduces myoblast proliferation and migration (Serrano et al., 2008).”
BackgroundSilva, C. M. S., Vieira, R. C., Trombeta, J. C. D. S., Lima, T. R., Fraga, G. A., Sena, M. D. S., Ávila, E. T. P., Tibana, R. A., Prestes, J., Navalta, J. W., et al. (2016) · Revista Andaluza de Medicina del Deporte · doi:10.1016/j.ramd.2016.02.005 · Cited by 8
Pleiotropic actions of Vitamin D in composite musculoskeletal trauma
Valerio, M. S., Janakiram, N. B., Goldman, S. M., & Dearth, C. L. (2020) · Injury · doi:10.1016/j.injury.2020.06.023 · Cited by 7
Pro-regenerative Dialogue Between Macrophages and Mesenchymal Stem/Stromal Cells in Osteoarthritis
Bohaud, C., Contreras-López, R. A., Cruz, J. D. L., Terraza‐Aguirre, C., Wei, M., Djouad, F., & Jørgensen, C. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.718938 · Cited by 8
Skeletal Muscle as Endocrine Organ
Ma, M., Zhang, Z., Hai, B., & Zhang, Y. (2025) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-88361-3_22 · Cited by 9
Cha, M., Bak, H., Bai, S. J., Lee, B. H., & Jang, J. H. (2024) · Regenerative Biomaterials · doi:10.1093/rb/rbae077 · Cited by 8
“At M-W1, a significant increase in satellite cell number and activation, as evidenced by elevated PAX7 and MyoD expression (Figure 5B and H), indicated initiated muscle recovery, accompanied by higher levels of satellite cell activators such as IL-6 [53] and IGF-1 [54] (Figure 6B).”
Lokwani, R., Fertil, D., Hartigan, D. R., Josyula, A., Ngo, T. B., & Sadtler, K. (2024) · Advanced Healthcare Materials · doi:10.1002/adhm.202400134 · Cited by 8
IL-6 Inhibitors and TNF Inhibitors
Jønck, S., Adamsen, M. L., Rasmussen, I. E., Lytzen, A. A., Løk, M., Lund, M. A. V., Dreyer, L., Jørgensen, P. G., Vejlstrup, N. G., Køber, L., et al. (2025) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2024.11.010 · Cited by 6
Martinelli, A., Andreo, L., Alves, A. N., Terena, S. M. L., Santos, T., Bussadori, S., Fernandes, K., & Mesquita-Ferrari, R. (2020) · Lasers in Medical Science · doi:10.1007/s10103-020-03095-y · Cited by 5
“[41] demonstrated the importance of IL-6 for muscle hypertrophy and myogenesis since the CH was induced in the plantaris muscle of mice using the synergist ablation model and the authors”
MethodOllewagen, T., Powrie, Y. S. L., Myburgh, K. H., & Smith, C. (2021) · Physiological Reports · doi:10.14814/phy2.15119 · Cited by 5
“IL- 6, as a myokine has exhibited both pro- and anti- inflammatory effects within the muscle (Muñoz- Cánoves et al., 2013), as well as exhibiting both hypertrophic effects through the stimulation of satellite cell proliferation (Serrano et al., 2008), and the promotion of atrophy.”
BackgroundMarr, E. E., Isenberg, B. C., & Wong, J. Y. (2023) · Bioactive Materials · doi:10.1016/j.bioactmat.2023.10.006 · Cited by 6
“It was found that different strain rates significantly impacted gene expression of IL-6, a marker for the inflammatory cytokine upregulated in certain cases of preterm labor [35,37,49] (Fig.”
BackgroundMyokines: A central point in managing redox homeostasis and quality of life
Rathor, R., & Suryakumar, G. (2024) · BioFactors · doi:10.1002/biof.2054 · Cited by 6
“Serrano et al., 175 reported an anabolic feature of IL-6 in myogenesis.”
Annibalini, G., Guescini, M., Agostini, D., Matteis, R. D., Sestili, P., Tibollo, P., Mantuano, M., Martinelli, C., & Stocchi, V. (2012) · BMB Reports · doi:10.5483/bmbrep.2012.45.1.32 · Cited by 6
Non-Synaptic Roles of Acetylcholinesterase and Agrin
Gros, K., Parato, G., Pirkmajer, S., Miš, K., Podbregar, M., Grubič, Z., Lorenzon, P., & Marš, T. (2013) · Journal of Molecular Neuroscience · doi:10.1007/s12031-013-0188-0 · Cited by 6
Scratch wound closure of myoblasts and myotubes is reduced by inflammatory mediators
Ko, M.-H., Li, C.-Y., Lee, C.-F., Chang, C.-K., & Fang, S.-H. (2016) · International Wound Journal · doi:10.1111/iwj.12346 · Cited by 5
“A number of studies have reported that IL-6 is involved in the process of myogenic proliferation (19) and differentiation (18).”
BackgroundAdenosine A2B Receptors - Mediated Induction of Interleukin-6 in Skeletal Muscle Cells
Haddad, M. (2017) · Turkish Journal of Pharmaceutical Sciences · doi:10.4274/tjps.08108 · Cited by 6
Mesenchymal Stem Cells Alter the Inflammatory Response of C2C12 Mouse Skeletal Muscle Cells
Kono, Y., Miyamoto, A., Hiraoka, S., Negoro, R., & Fujita, T. (2020) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b20-00536 · Cited by 7
Ergogenic effects of caffeine are mediated by myokines
Takada, S., Fumoto, Y., & Kinugawa, S. (2022) · Frontiers in Sports and Active Living · doi:10.3389/fspor.2022.969623 · Cited by 6
“Although the results are controversial, IL-6 also is involved in muscle hypertrophy and myogenesis (28, 36).”
BackgroundÇınar, G., Mumcuoğlu, D., Tekinay, A. B., & Güler, M. O. (2016) · Wiley eBooks · doi:10.1002/9781118987483 · Cited by 6
Minari, A. L. A., Oyama, L., & dos Santos, R. V. T. (2017) · Journal of Muscle Research and Cell Motility · doi:10.1007/s10974-017-9475-7 · Cited by 6
“This hypothesis is supported by several studies, including IL-10 and IL-6 knockout mice and myoblast culture, where the presence of these molecules was fundamental for adequate skeletal muscle regeneration (Arnold et al. 2007; Deng et al. 2012; Serrano et al. 2008; Snijders et al. 2015).”
ResultLi, Q., Lin, J., Rosen, S. M., Zhang, T., Kazerounian, S., Luo, S., & Agrawal, P. B. (2020) · American Journal Of Pathology · doi:10.1016/j.ajpath.2020.08.012 · Cited by 6
Dlamini, S. N., Norris, S. A., & Micklesfield, L. K. (2025) · British Journal Of Nutrition · doi:10.1017/s0007114525000029 · Cited by 5
“GGH plays a role in folate metabolism and thus indirectly influences the synthesis of both amino acids and nucleotides – which are important in cellular growth and replication (56) .”
Metadata
- Authors
- Serrano, A. L., Baeza-Raja, B., Perdiguero, E., Jardí, M., & Muñoz-Cánoves, P.
- Affiliations
- Universitat Pompeu Fabra (ES)
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2008-01
- Volume
- 7
- Issue
- 1
- Pages
- 33-44
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W1997149085
- Cited by
- 873
- References
- 57
- Citations by year
- 2026: 43 · 2025: 56 · 2024: 42 · 2023: 55 · 2022: 71 · 2021: 73 · 2020: 48 · 2019: 55 · 2018: 50 · 2017: 54 · 2016: 45 · 2015: 69 · 2014: 42 · 2013: 48 · 2012: 51
- FWCI
- 9.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2024 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Association Française contre les Myopathies (Marató-TV3)
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
- Muscular Dystrophy Association
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Nursing › Nutrition and Dietetics › Muscle metabolism and nutrition
- Keywords
- interleukin-6, satellite cells, skeletal muscle hypertrophy, muscle stem cells, STAT3 signaling, cyclin D1, myonuclear accretion, satellite cell proliferation, paracrine signaling, myofiber growth, cytokine deficiency
- MeSH terms
- Animals, Cell Line, Cell Movement, Enzyme-Linked Immunosorbent Assay, Hypertrophy, Immunohistochemistry, Muscular Diseases, Blotting, Western, Interleukin-6, Mice, Knockout, Muscle, Skeletal, Muscle Fibers, Skeletal, Cyclin D1, Reverse Transcriptase Polymerase Chain Reaction, Myoblasts, Satellite Cells, Skeletal Muscle, Cell Proliferation, STAT3 Transcription Factor, Mice
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