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Interleukin 6 receptor antibody inhibits muscle atrophy and modulates proteolytic systems in interleukin 6 transgenic mice.
Open accessAbstract
The muscles of IL-6 transgenic mice suffer from atrophy. Experiments were carried out on these transgenic mice to elucidate activation of proteolytic systems in the gastrocnemius muscles and blockage of this activation by treatment with the anti-mouse IL-6 receptor (mIL-6R) antibody. Muscle atrophy observed in 16-wk-old transgenic mice was completely blocked by treatment with the mIL-6R antibody. In association with muscle atrophy, enzymatic activities and mRNA levels of cathepsins (B and L) and mRNA levels of ubiquitins (poly- and mono-ubiquitins) increased, whereas the mRNA level of muscle-specific calpain (calpain 3) decreased. All these changes were completely eliminated by treatment with the mIL-6R antibody. This IL-6 receptor antibody could, therefore, be effective against muscle wasting in sepsis and cancer cachexia, where IL-6 plays an important role.
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“the pilot study of Tsujinaka and colleagues showed that transgenic mice chronically overexpressing IL-6 exhibit a marked muscle atrophy [47]; however, the knockout of IL-6 was not sufficient to prevent sarcopenia in a sepsis mouse model [48].”
From Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting (2023) · cites this paper as [47]
In the citing paper
“However, it has also been shown that proinflammatory cytokines may inhibit muscle progenitor cell differentiation and that the reactive oxygen species that are produced by M1 cells (nitric oxide) can be cytotoxic if present in sufficient quantities, demonstrating the need for resolution of the proinflammatory response for muscle recovery to proceed beyond this initial stage [120–122].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [122]
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BackgroundCoffee treatment prevents the progression of sarcopenia in aged mice in vivo and in vitro
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“The overexpression of IL-6 in transgenic mice caused muscular atrophy and increased levels of cathepsin in skeletal muscle, indicating that IL-6 is involved in the regulation of muscle protein degradation (37).”
BackgroundAnorexia in cancer: role of feeding-regulatory peptides
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“This contrasts to recent data suggesting that IL-6 could directly activate muscle proteolysis and especially the lysosomal and ATP-ubiquitin-dependent pathways (16, 32).”
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BackgroundPhysiological role of cytokines in the regulation of mammalian metabolism
Baat, A. D., Trinh, B., Ellingsgaard, H., & Donath, M. Y. (2023) · Trends in Immunology · doi:10.1016/j.it.2023.06.002 · Cited by 62
Erythropoietin in cancer: a dilemma in risk therapy
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“Results in other tissues suggest a stimulatory effect of IL-6 (Tsujinaka et al. 1996), which does indeed happen with one of the probe sets (162271_f_at).”
BackgroundMoore‐Carrasco, R., Busquets, S., Almendro, V., Palanki, M. S. S., López-Soriano, F. J., & Argilés, J. M. A. (2007) · International Journal of Oncology · doi:10.3892/ijo.30.5.1239 · Cited by 57
Behavioral Effects of Infection with IL-6 Adenovector
Šakić, B., Gauldie, J., Denburg, J. A., & Szechtman, H. (2001) · Brain Behavior and Immunity · doi:10.1006/brbi.1999.0576 · Cited by 56
Effects of arachidonic acid supplementation on training adaptations in resistance-trained males
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“psin, and ubiquitin pathways [44-48].”
Aberrant Myokine Signaling in Congenital Myotonic Dystrophy
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“A transgenic mouse model that overexpresses IL-6 displayed severe muscle atrophy, and blockade of IL-6 signaling by treatment with an IL-6R antibody reversed the muscle phenotype (Tsujinaka et al., 1995; Tsujinaka et al., 1996).”
BackgroundStenvinkel, P., Lindholm, B., & Heimbürger, O. (2004) · Seminars in Dialysis · doi:10.1111/j.0894-0959.2004.17611.x · Cited by 54
“of muscle protein (40) and promote cancer-related wasting (41), while the administration of IL-6 receptor antibody has been shown to inhibit muscle atrophy that occurs in IL-6 transgenic mice (42).”
BackgroundRole of Inflammation and Its Treatment in ESRD Patients
Kaysen, G. A. (2002) · Blood Purification · doi:10.1159/000046988 · Cited by 54
A new model of cancer cachexia: contribution of the ubiquitin-proteasome pathway
Lazarus, D. D., Destree, A. T., Mazzola, L. M., McCormack, T. A., Dick, L. R., Xu, B. H., Huang, J. Q., Pierce, J. W., Read, M. A., Coggins, M. B., et al. (1999) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1999.277.2.e332 · Cited by 53
Are antioxidants useful for treating skeletal muscle atrophy?
Bonetto, A., Penna, F., Muscaritoli, M., Minero, V. G., Fanelli, F. R., Baccino, F. M., & Costelli, P. (2009) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.07.002 · Cited by 53
“tion achieved in transgenic mice increases the expression of components of the ATP–ubiquitin-dependent proteolytic systems [22].”
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Toll-like Receptor 4 Signaling in Ventilator-induced Diaphragm Atrophy
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“For example, overexpression of IL-6 in transgenic mice engenders profound skeletal muscle atrophy, which can be completely blocked by administration of an IL-6 antagonist.(21) Subcutaneous administration of IL-6 also results in skeletal muscle atrophy in rats.”
BackgroundMalnutrition in patients with chronic kidney disease
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“Increased muscle wasting was noted in murine models following high-dose or long-term treatment with IL-6 [82].”
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Calpain 3 mRNA expression in mice after denervation and during muscle regeneration
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“Calpain 3 seems to play a counterregulatory role (34).”
BackgroundCancer cachexia: molecular basis and therapeutic advances
Tan, Y., Xue, R., Pan, Y., he, Z., Hu, X., Li, Y., Li, K., Zhang, X., Bian, X.-W., & Wang, B. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02331-7 · Cited by 57
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“Administering IL-6 receptor antibodies prevented these effects in mice transgenic for IL-6 [46].”
Regulation of interleukin-6 secretion from breast cancer cells and its clinical implications
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Expression of three calpain isoform genes in human skeletal muscles
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“270, 2497–2505. ing muscular atrophy (Tsujinaka et al., 1996).”
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Tumor inoculation site affects the development of cancer cachexia and muscle wasting
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“Prior in vitro and in vivo studies have demonstrated that IL-6 plays an important role in muscle degradation by activating both ubiquitins and cathepsins which are responsible for the proteolytic pathways.(37,38) Our study supports this notion and we believe that an increase in circulating IL-6 was highly involved in…”
BackgroundIL-6, cancer and cachexia: metabolic dysfunction creates the perfect storm
White, J. P. (2017) · Translational Cancer Research · doi:10.21037/tcr.2017.03.52 · Cited by 45
“Transgenic mice over-expressing circulating IL-6 show muscle atrophy associated with increased expression of lysosomal and ubiquitin-related mRNA and proteins (14,15).”
BackgroundAssociation Between Interleukin-6 and Head and Neck Squamous Cell Carcinoma: A Systematic Review
Uz, U., & Eskiizmir, G. (2021) · Clinical and Experimental Otorhinolaryngology · doi:10.21053/ceo.2019.00906 · Cited by 43
“In experimental models, elevated IL-6 concentrations have been correlated with muscular atrophy, weight loss and hypophagia [66,67].”
BackgroundCancer-Associated Cachexia: A Systemic Consequence of Cancer Progression
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Review Articles: Uremic Malnutrition: New Insights Into an Old Problem
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The E3 ubiquitin ligase TRIM62 and inflammation-induced skeletal muscle atrophy
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The Impact of Sarcopenia on Cervical Spine Sagittal Alignment After Cervical Laminoplasty
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Canpolat, N., Çalışkan, S., Sever, L., Taşdemir, M. S., Ekmekçi, Ö. B., Pehlivan, G., & Shroff, R. C. (2013) · Pediatric Nephrology · doi:10.1007/s00467-013-2527-3 · Cited by 41
“Given that IL-6 plays a central role in inflammation [36], and is also associated with increased muscle proteolysis [37], our results indicate a clear association between inflammation and poor nutritional status in children and adolescents on maintenance dialysis.”
Metadata
- Authors
- Tsujinaka, T., Fujita, J., Ebisui, C., Yano, M., Kominami, E., Suzuki, K., Tanaka, K., Katsume, A., Ohsugi, Y., Shiozaki, H., & Monden, M.
- Affiliations
- Osaka University Hospital (JP)
- The University of Osaka (JP)
- Juntendo University (JP)
- Institute for Quantitative Biosciences, The University of Tokyo (JP)
- Chugai Pharmaceutical Co., Ltd. (Japan) (JP)
- Venue
- Journal of Clinical Investigation
- Published
- 1996-01-01
- Volume
- 97
- Issue
- 1
- Pages
- 244-249
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC507086
- OpenAlex
- W2060757943
- Cited by
- 421
- References
- 57
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 16 · 2023: 10 · 2022: 22 · 2021: 16 · 2020: 13 · 2019: 9 · 2018: 14 · 2017: 11 · 2016: 9 · 2015: 17 · 2014: 9 · 2013: 14 · 2012: 18
- FWCI
- 5.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology (medical) › Nutrition and Health in Aging
- Health Sciences › Nursing › Nutrition and Dietetics › Muscle metabolism and nutrition
- Keywords
- interleukin-6, IL-6 receptor antibody, muscle atrophy, proteolytic system, cathepsin B, cathepsin L, ubiquitin, CAPN3, gastrocnemius, cancer cachexia, sepsis
- MeSH terms
- Animals, Antibodies, Monoclonal, Body Weight, Calpain, Cathepsin B, Cathepsins, Cysteine Endopeptidases, Humans, Mice, Inbred C57BL, Mice, Transgenic, Multienzyme Complexes, Muscular Atrophy, Organ Size, Endopeptidases, RNA, Messenger, Ubiquitins, Antigens, CD, Interleukin-6, Gene Expression, Rats, Wistar, Receptors, Interleukin, Muscle, Skeletal, Receptors, Interleukin-6, Proteasome Endopeptidase Complex, Mice, Rats, Cathepsin L
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