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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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BackgroundUrine-derived stem cells genetically modified with IGF1 improve muscle regeneration
Yi, H. (2024) · American Journal of Clinical and Experimental Urology · doi:10.62347/qskh2686 · Cited by 4
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InfluentialMusculoskeletal and neuromuscular dysfunction due to covid-19 infection: A review
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MethodTHE EFFECT OF MUSCLE DAMAGE AND THE IL-6-174C/G POLYMORPHISM ON THE SERUM IL-6 LEVELS OF OLDER MEN
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“25,30 Thus, the altered downregulation of these inflammation-related genes may negatively affect the rotator cuff muscles.”
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“For example, short-term exercise-induced IL-6 exerts anti-in fl ammatory effects, enhances glucose utilization, and promotes MuSC proliferation (39, 40).”
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BackgroundMyokines Produced by Cultured Bovine Satellite Cells Harvested from 3- and 11-Month-Old Angus Steers
Shira, K. A., Murdoch, B. M., Thornton, K. J., Reichhardt, C. C., Becker, G. M., Chibisa, G. E., & Murdoch, G. K. (2024) · Animals · doi:10.3390/ani14050709 · Cited by 3
“Irisin regulates glucose uptake by muscle cells by stimulating the translocation of GLUT4 to the cell surface in a similar manner to IL-6 and insulin [28].”
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“Muscle satellite cells are activated and induce adaptive changes of skeletal muscle such as hypertrophy, the alteration of fiber type, and regeneration by external stimuli such as mechanical loading, unloading, denervation, and injury through growth factors such as IGFs, myostatin and IL-6 [16,21-23,32,33].”
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“64 HGF can activate quiescent satellite cells and drive them into cell cycle in vitro and in vivo.”
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BackgroundBranine, M. E., Schilling-Hazlett, A. K., Carvalho, P. H. V., Stackhouse-Lawson, K. R., Martins, E. C., da Silva, J. T., Amundson, L. A., Ashworth, C., Socha, M. T., & Dridi, S. (2025) · Veterinary Sciences · doi:10.3390/vetsci12010065 · Cited by 2
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“In addition, knocking out IL6 impairs satellite cell proliferation by decreasing STAT3 phosphorylation and cyclinD1 expression [31].”
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“…tissue growth factor (CTGF) [30], which amplifies the pro-fibrotic response; the imbalance between matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) [31], which governs ECM remodeling; and key inflammatory cytokines (e.g., IL-6 [32], TNF-α [31]) that initiate the fibrotic cascade.”
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The role of mitochondrial function in skeletal muscle and myokines in the pathogenesis of sarcopenia
Sugimoto, K. (2012) · Nippon Ronen Igakkai Zasshi Japanese Journal of Geriatrics · doi:10.3143/geriatrics.49.199 · Cited by 2
Keller, S., Kohne, S., Notbohm, H. L., Bloch, W., & Schumann, M. (2021) · International Journal of Sports Physiology and Performance · doi:10.1123/ijspp.2020-0509 · Cited by 2
Obesity, Myokines, and Metabolic Health
Malandrino, N., & Ahima, R. S. (2023) · Springer eBooks · doi:10.1007/978-3-031-40116-9_56 · Cited by 2
Vasconcelos, E. D. S. (2018) · MOJ Sports Medicine · doi:10.15406/mojsm.2018.02.00048 · Cited by 2
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Health benefits of aerobic exercise: known mechanisms and research potential
Begrambekova, Y. L., & Orlova, Y. A. (2021) · CARDIOVASCULAR THERAPY AND PREVENTION · doi:10.15829/1728-8800-2021-2878 · Cited by 3
Dahlquist, D. T. (2016) · cIRcle (University of British Columbia) · doi:10.14288/1.0305021 · Cited by 2
Amphiregulin mediates non-cell-autonomous effect of senescence on reprogrammingPreprint
von Joest, M., Chen, C., Douché, T., Chiche, A., Matondo, M., & Li, H. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.09.01.458621 · Cited by 2
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Myokine Expression in Cancer Cachexia
Manole, E., Ceafalan, L. C., Gaina, G. F., Mosoia, O., & Hinescu, M. E. (2023) · Interdisciplinary cancer research · doi:10.1007/16833_2023_138 · Cited by 1
Machado-Pereira, N. A. M. M., do Nascimento, P. S., de Freitas, G. R., Bobinski, F., Santo, C. C. D. E., & Ilha, J. (2024) · Revista Brasileira de Ortopedia · doi:10.1055/s-0044-1787767 · Cited by 2
EPA but not DHA prevents lipid metabolism disorders by regulating myogenic IL-6 in high-fat fed mice
Xie, Q., Mao, L., Xiong, N., Cheng, Q., Tang, W., Li, C., Zeng, C., Liu, Z., & Mao, L. (2024) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2024.109815 · Cited by 1
Tajik, A., Mahdavizadeh, V., Hadizadeh, F., & Shakour, N. (2025) · Current Diabetes Reviews · doi:10.2174/0115733998349193250207045239 · Cited by 1
Yang, H., Zheng, Y., Yu, T., Wu, B., Liu, Z., Liu, S., Sun, X., & Zhou, L. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.142308 · Cited by 1
HDAC11 deficiency regulates age-related muscle decline and sarcopenia
Odria, R., Cardús, A., Gomis-Coloma, C., Balanyà-Segura, M., Mercado-Amarilla, A., Maestre-Mora, P., Sabuco, A. P., Domingo, J. C., Nogales‐Gadea, G., Gomez-Sanchez, J. A., et al. (2025) · GeroScience · doi:10.1007/s11357-025-01611-y · Cited by 1
“Local transient production of IL-6 after stimuli has been found essential for SC proliferation and hypertrophic growth [52].”
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Mykles, D. L., Musgrove, L., & Ventura, T. (2025) · Elsevier eBooks · doi:10.1016/b978-0-323-95424-2.00009-1 · Cited by 1
Role of Myokines on the Bone Metabolism of Craniofacial Region: A Scoping Review
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Trinh, B., Rasmussen, S. J., Brøgger-Jensen, M. E., Tavanez, A. R., Lund, A., Vassilieva, A., Janum, S., Iepsen, U. W., Møller, K., Pedersen, B. K., et al. (2025) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaf547 · Cited by 3
Valle-Clara, M., & Ávila, G. (2025) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00509.2025 · Cited by 1
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“Interestingly, IL-6 is further subjected to regulate the SC proliferation capacity (Serrano et al .”
Odria, R., Mercado-Amarilla, A., Soler‐Botija, C., Borràs, D., Ohana, J., Maestre-Mora, P., Bigot, A., Suárez‐Calvet, X., Gallardo, E., Nogales‐Gadea, G., et al. (2025) · Life Sciences · doi:10.1016/j.lfs.2025.124150 · Cited by 1
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“However, IL6 is also increased in response to exercise and contributes to hypertrophy as IL-6 -/- mice have a reduced hypertrophic response to overload with reduced myonuclear accretion [14].”
Silva-de-Oliveira, A. F. S., da Silva, J. L., dos Santos, N. T. B., Andraus, R. A. C., Poli‐Frederico, R. C., Oliveira, D. A. D. A. P., de Oliveira, R. F., & Luciana Prado, M. A. I. A. (2026) · Lasers in Medical Science · doi:10.1007/s10103-026-04811-w · Cited by 1
“However, when chronically elevated, IL-6 is associated with muscle wasting and impaired regeneration [3–5].”
BACH1 orchestrates macrophage state transitions to coordinate regenerative inflammation
Caballero-Sánchez, N., Tzerpos, P., Bene, K., Halász, L., Bojcsuk, D., Nagy, G., Ali, M. A., Cseh, T., Póliska, S., Borok, M. J., et al. (2026) · The Journal of Immunology · doi:10.1093/jimmun/vkag101 · Cited by 1
“42 In this vein, we hypothesized that the loss of BACH1 in immune cells might lead to altered paracrine signaling that influences MuSC fate decisions during regeneration.”
Two‐Way Communication Between Skeletal Muscle and Myokines
Huang, T., Zhou, S., Chen, X., Chen, D., Yu, B., & Huang, Z. (2026) · Cell Biochemistry and Function · doi:10.1002/cbf.70267 · Cited by 1
“After a decade, a remarkable study reported that IL‐6 promoted skeletal muscle hypertrophy by promoting the proliferation of skeletal muscle satellite cells and myoblasts, and further exploration found that STAT3 is the main effector of IL‐6 to promote muscle cell growth [31].”
Single-cell resolution of skeletal muscle aging: Current paradigms and perspectives
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Frailty and COPD: a bidirectional relationship in the context of systemic and accelerated ageing
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“Physical inactivity further aggravates this imbalance by reducing the beneficial secretion of exercise-induced myokines involved in muscle maintenance and metabolic regulation [109].”
Ameis, K., Jayam, A., Bond, V., & Yasmine, K. (2011) · InTech eBooks · doi:10.5772/24801 · Cited by 1
“Loss of IL-6 results in reduced satellite cell proliferation and migration (Serrano et al., 2008).”
Srf : un acteur clé de l’hypertrophie du muscle squelettique
Guerci, A., Lahoute, C., Hébrard, S., Collard, L., Daegelen, D., & Sotiropoulos, A. (2012) · médecine/sciences · doi:10.1051/medsci/2012285008 · Cited by 1
“En particulier, les myokines sécrétées par les myofibres telles que l’IL(interleukine)-6 et l’IL-4 modulent respectivement la prolifération et la fusion des progéniteurs musculaires [3, 4].”
BackgroundLuchetti, F., Nasoni, M. G., Falcieri, E., & Mendes, A. F. (2018) · Journal of Functional Morphology and Kinesiology · doi:10.3390/jfmk3030042 · Cited by 1
“Muscle satellite cells (mSCs) are examples of adult stem cells for skeletal muscles.”
BackgroundInfluential
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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