Cited by 421Muscle Physiology and DisordersNutrition and Health in AgingMuscle metabolism and nutrition

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Interleukin 6 receptor antibody inhibits muscle atrophy and modulates proteolytic systems in interleukin 6 transgenic mice.

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Tsujinaka, T, Fujita, J, Ebisui, C, Yano, M, Kominami, E, Suzuki, K, Tanaka, K, Katsume, A, Ohsugi, Y, Shiozaki, H, Monden, M·1996·Journal of Clinical Investigation

DOI 10.1172/jci118398PMC PMC507086

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Abstract

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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Background
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Sarcopenia and Cachexia in Older Patients with Cancer: Pathophysiology, Diagnosis, Impact on Outcomes, and Management Strategies
Papadopoulos, E., Irving, B. A., Brown, J. C., Heymsfield, S. B., Sattar, S., Alibhai, S. M. H., Williams, G. R., & Dunne, R. F. (2025) · Drugs & Aging · doi:10.1007/s40266-025-01252-y · Cited by 28
“The deleterious effects of IL-6 on the skeletal muscle have further been exemplified by mechanistic work, where treatment of IL-6 transgenic mice with anti-mouse IL-6 receptor antibody abolished the observed muscle atrophy and associated perturbations in proteolytic pathways [155].”
Interleukin 6 (IL6) level is a biomarker for functional disease progression within IL6R358Ala variant groups in amyotrophic lateral sclerosis patients
Wosiski‐Kuhn, M., Caress, J. B., Cartwright, M. S., Hawkins, G. A., & Milligan, C. (2020) · Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration · doi:10.1080/21678421.2020.1813310 · Cited by 25
“Muscle atrophy that follows denervation is associated with increased expression of IL6 (3,14,17,37,56,57).”
Background
Inhibition of monocyte chemoattractant protein-1 prevents diaphragmatic inflammation and maintains contractile function during endotoxemia
Labbè, K., Danialou, G., Gvozdic, D., Demoule, A., Divangahi, M., Boyd, J. H., & Petrof, B. J. (2010) · Critical Care · doi:10.1186/cc9295 · Cited by 25
“IL-1 significantly decreases muscle weight, protein content, and the rate of protein synthesis in skeletal muscle [36], whereas IL-6 can upregulate the cathepsin and ubiquitin pathways of muscle proteolysis [37].”
Background
Enhanced excitation-coupled Ca2+ entry induces nuclear translocation of NFAT and contributes to IL-6 release from myotubes from patients with central core disease
Treves, S., Vukcevic, M., Jeannet, P., Levano, S., Girard, T., Urwyler, A., Fischer, D., Voït, T., Jungbluth, H., Lillis, S., et al. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq506 · Cited by 25
“patients with CCD and other neuromuscular disorders may help shed light into some of the pathological alterations seen in patients with ryanodinopathies such as muscle cramping and muscle protein breakdown (49,50).”
Background
Lifelong Caloric Restriction and Interleukin-6 Secretion From Adipose Tissue: Effects on Physical Performance Decline in Aged Rats
You, T., Sonntag, W. E., Leng, X., & Carter, C. S. (2007) · The Journals of Gerontology Series A · doi:10.1093/gerona/62.10.1082 · Cited by 25
“Indeed, administration of IL-6 causes muscle atrophy (30), whereas administration of anti-IL-6 receptor antibody prevents the muscle atrophy in these animals (31,32).”
Background
The role of interleukin‐6 family cytokines in cancer cachexia
Agca, S., & Kır, S. (2024) · FEBS Journal · doi:10.1111/febs.17224 · Cited by 26
“In fact, the use of antibodies neutralizing IL-6 ameliorated muscle wasting in different models of cancer cachexia [48,56 – 59].”
Comparative Effects of Basic Fibroblast Growth Factor Delivery or Voluntary Exercise on Muscle Regeneration after Volumetric Muscle Loss
Hu, C., Ayan, B., Chiang, G., Chan, A., Rando, T. A., & Huang, N. F. (2022) · Bioengineering · doi:10.3390/bioengineering9010037 · Cited by 24
“For example, although bFGF and exercise can induce muscle satellite cell proliferation by the activation of signal transducer and activator of transcription 3 (STAT3) signaling [37,38], the tuning of STAT3 expression is critically important, as prolonged STAT3 expression has opposing effects of inducing muscle atrophy…”
Background
Retrospective analysis of the preparation and application of immunotherapy in cancer treatment (Review)
Lu, J., Ding, J., Liu, Z., & Chen, T. (2022) · International Journal of Oncology · doi:10.3892/ijo.2022.5302 · Cited by 24
“mAbs against the human IL‐6 receptor can show strong antitumour activity in vivo against multiple myeloma cells by inhibiting IL‐6 functions (87).”
BackgroundMethod
Effect of Nutrient Restriction and Re-Feeding on Calpain Family Genes in Skeletal Muscle of Channel Catfish (Ictalurus punctatus)
Preziosa, E., Liu, S., Terova, G., Gao, X., Liu, H., Kucuktas, H., Terhune, J. S., & Liu, Z. (2013) · PLoS ONE · doi:10.1371/journal.pone.0059404 · Cited by 23
“Similar results have been obtained in previous studies [56] in which a decrease in clpn3 gene expression in skeletal muscle of interleukin-6 (IL-6) was observed in transgenic mice suffering from atrophy of both red and white muscles.”
Result
Cellular proteolysis and systemic inflammation during exacerbation in cystic fibrosis
Ionescu, A., Nixon, L. S., & Shale, D. J. (2004) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2004.07.003 · Cited by 23
“The transgenic IL-6 mouse constitutively secretes IL-6 and develops a severe proteolytic myopathy, which was reversed by an IL-6 receptor blocking antibody [15].”
Background
Nitric Oxide Stimulates Interleukin-6 Production in Skeletal Myotubes
Makris, A. C., Sotzios, Y., Zhou, Z., Makropoulou, M., Papapetropoulos, N., Zacharatos, P., Pyriochou, A., Roussos, C., Papapetropoulos, A., & Vassilakopoulos, T. (2009) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2009.0022 · Cited by 23
The therapeutic potential of interleukin-6 hyperagonists and antagonists
Kallen, K.-J., Büschenfelde, K. M. Z., & Rose‐John, S. (1997) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.6.3.237 · Cited by 23
Inflammatory cytokines and malnutrition as related to risk for cardiovascular disease in hemodialysis patientsThis article is one of a selection of papers published in the special issue Bridging the Gap: Where Progress in Cardiovascular and Neurophysiologic Research Meet.
Peruničić-Peković, G., Pljesa, S., Rašić-Milutinović, Z., Stankovic, S. D., Ilic, M., & Maletić, R. (2008) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y08-018 · Cited by 22
“Increased activation of inflammatory cytokines, such as IL-6 and TNF-a, may cause muscle breakdown and hypoalbuminemia and may be involved in atherogenesis (Bologa et al. 1998; Ebisui et al. 1995; Kaizu et al.1998; Ross 1999; Stenvinkel 2001b; Tsujinaka et al. 1996).”
Background
Effects of Interleukin-1β and -6 on the Expression of Ion Transporters Involved in Eggshell Mineralization in Cultured Hen Uterine Mucosal Tissue
Nii, T., Isobe, N., & Yoshimura, Y. (2017) · The Journal of Poultry Science · doi:10.2141/jpsa.0170138 · Cited by 21
“Studies have suggested protein degradation mediated by IL6 in muscle cells through the enhancement of proteolytic factors in mammals (Tsujinaka et al., 1996; Zoico and Roubenoff, 2002; Narsale and Carson, 2014).”
Background
Clinical characteristics of geriatric patients with non-specific chronic low back pain
Sakai, Y., Wakao, N., Matsui, H., Watanabe, T., Iida, H., & Watanabe, K. (2022) · Scientific Reports · doi:10.1038/s41598-022-05352-2 · Cited by 23
Combination of Telmisartan with Cisplatin Controls Oral Cancer Cachexia in Rats
Patel, B. M., & Damle, D. (2013) · BioMed Research International · doi:10.1155/2013/642848 · Cited by 21
Depletion of Circulating Insulin-Like Growth Factor Binding Protein 3 After Open Surgery is Associated With High Interleukin-6 Levels
Kirman, I., Poltaratskaia, N., Cekic, V., Forde, K. A., Ansari, P., Boulay, C., & Whelan, R. L. (2004) · Diseases of the Colon & Rectum · doi:10.1007/s10350-004-0512-4 · Cited by 21
Understanding cachexia and its impact on lung cancer and beyond
Yue, M., Qin, Z., Hu, L., & Ji, H. (2024) · Chinese Medical Journal - Pulmonary and Critical Care Medicine · doi:10.1016/j.pccm.2024.02.003 · Cited by 21
“50–55 Animal experiments have further demonstrated that IL-6 is suﬃcient to induce cachexia.”
Prolonged mechanical ventilation worsens sepsis-induced diaphragmatic dysfunction in the rat
Dinh, M. L., Carreira, S., Obert, J., Gayan‐Ramirez, G., Riou, B., Beuvin, M., Similowski, T., Coirault, C., & Demoule, A. (2018) · PLoS ONE · doi:10.1371/journal.pone.0200429 · Cited by 20
“IL-6 upregulates cathepsin and ubiquitin, two pathways of muscle proteolysis [25] although it may also have beneficial effects on myogenesis through regulation of the proliferative capacity of muscle stem cells on regulation of energy metabolism [26].”
Background
Factors associated with pain-related disorders and gait disturbance scores from the Japanese orthopedic association back pain evaluation questionnaire and Oswestry Disability Index in patients with osteoporosis
Miyagi, M., Inoue, G., Murata, K., Koyama, T., Kuroda, A., Kawakubo, A., Yokozeki, Y., Mimura, Y., Nanri, Y., Inage, K., et al. (2021) · Archives of Osteoporosis · doi:10.1007/s11657-021-01045-x · Cited by 22
Lean and fat mass as determinants of muscle strength and insulin sensitivity in Chilean elderly subjects.
Bunout, D. C., Barrera, G., Maza, T. D. L., Avendaño, M., Gattas, V., Petermann, M., & Hirsch, S. (2004) · PubMed · Cited by 20
Interleukin-6 in neuroimmunological disorders: Pathophysiology and therapeutic advances with satralizumab
Li, X., & Zhao, C. (2025) · Autoimmunity Reviews · doi:10.1016/j.autrev.2025.103826 · Cited by 21
Coordinate expression of the 19S regulatory complex and evidence for ubiquitin-dependent telethonin degradation in the unloaded soleus muscle
Heng, A.-É., Ventadour, S., Jarzaguet, M., Pouch-Pélissier, M.-N., Guezennec, C. Y., Bigard, X. A., Attaix, D., & Taillandier, D. (2008) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2008.04.013 · Cited by 19
The Role of Genetic Variation in Muscle Strength
Kostek, M. C., Hubal, M. J., & Pescatello, L. S. (2010) · American Journal of Lifestyle Medicine · doi:10.1177/1559827610387251 · Cited by 22
Ubiquitin and the Molecular Pathology of Human Disease
Mayer, R. J., Landon, M., & Lowe, J. S. (1998) · Springer eBooks · doi:10.1007/978-1-4899-1922-9_15 · Cited by 19
Effective therapy of polymyositis in mice via selective inhibition of the immunoproteasome
Oliva, M. D. R., Kirk, C. J., Groettrup, M., & Basler, M. (2022) · European Journal of Immunology · doi:10.1002/eji.202249851 · Cited by 18
HORSE SPECIES SYMPOSIUM: The aging horse: Effects of inflammation on muscle satellite cells
Reed, S. A., LaVigne, E. K., Jones, A. K., Patterson, D. F., & Schauer, A. L. (2014) · Journal of Animal Science · doi:10.2527/jas.2014-8448 · Cited by 18
New Aspect of the Research on Limb-Girdle Muscular Dystrophy 2A A Molecular Biologic and Biochemical Approach to Pathology
Ono, Y. (1999) · Trends in Cardiovascular Medicine · doi:10.1016/s1050-1738(99)00018-3 · Cited by 18
“5, 1999 117 physiologic function of p94 comes from a study on the effect of interleukin 6 (IL-6) in skeletal muscle (Tsujinaka et al. 1996).”
Background
Whole‐Body Protein Metabolism in Chronic Heart Failure: Relationship to Anabolic and Catabolic Hormones
Toth, M. J., & Matthews, D. E. (2006) · Journal of Parenteral and Enteral Nutrition · doi:10.1177/0148607106030003194 · Cited by 17
“The role of the IL-6 system in the development of cachexia has been demonstrated repeatedly.(42,43) The reason why IL-6sR, rather than IL-6, correlated with leucine oxidation, however, is not readily apparent.”
Background
A preliminary study on the role of Piezo1 channels in myokine release from cultured mouse myotubes
Sciancalepore, M., Massaria, G., Tramer, F., Zacchi, P., Lorenzon, P., & Bernareggi, A. (2022) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2022.07.059 · Cited by 17
["Malnutrition-inflammation complex syndrome" in chronic hemodialysis].
Young, P., Lombi, F., Finn, B. C., Forrester, M., Campolo-Girard, V., Pomeranz, V., Iriarte, R., Bruetman, J. E., & Trimarchi, H. (2011) · PubMed · Cited by 16
Role of the Renin–Angiotensin System in Age-Related Sarcopenia and Diastolic Dysfunction
Carter, C. S., & Groban, L. (2008) · Aging Health · doi:10.2217/1745509x.4.1.37 · Cited by 16
“Treatment with the IL-6-receptor antibody reverses muscle atrophy, enzymatic activity and reduces messenger RNA levels of cathepsin, and elevates messenger RNA level of both poly- and monoubiquitins in IL-6 transgenic mice [59].”
Background
Capecitabine improves cancer cachexia and normalizes IL-6 and PTHrP levels in mouse cancer cachexia models
Fujimoto-Ouchi, K., Onuma, E., Shirane, M., Mori, K., & Tanaka, Y. (2006) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-006-0338-y · Cited by 16
“Similar results that IL-6 is not the sole factor responsible for inducing cachexia were reported using IL-6 transgenic mice [37].”
Result
Histone Deacetylases as Modulators of the Crosstalk Between Skeletal Muscle and Other Organs
Renzini, A., D’Onghia, M., Coletti, D., & Moresi, V. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.706003 · Cited by 15
Muscle regeneration in gilthead sea bream: Implications of endocrine and local regulatory factors and the crosstalk with bone
Otero-Tarrazón, A., Perelló-Amorós, M., Jorge-Pedraza, V., Moshayedi, F., Sánchez-Moya, A., García-Pérez, I., Fernández‐Borràs, J., de la serrana, D. G., Navarro, I., Blasco, J., et al. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1101356 · Cited by 16
“Moreover, some studies support the fact that Il-6 also induces proteolysis of muscle cells by activating and modulating proteolytic systems (77, 78).”
Background
Cancer cachexia-anorexia syndrome and skeletal muscle wasting
Jurdana, M. (2009) · Radiology and Oncology · doi:10.2478/v10019-009-0007-y · Cited by 15
The Pro-Inflammatory Cytokine Cascade
Cavaillon, J., & Adib‐Conquy, M. (2002) · Springer eBooks · doi:10.1007/978-3-642-57210-4_4 · Cited by 15
Down‐regulation of the mitochondrial i‐AAA protease Yme1L induces muscle atrophy via FoxO3a and myostatin activation
Lee, Y. J., Kim, G. H., Park, S. I., & Lim, J. H. (2019) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.14799 · Cited by 15
Role of nutrition for cardiovascular risk reduction in chronic kidney disease patients
Ikizler, T. A. (2004) · Advances in Chronic Kidney Disease · doi:10.1053/j.arrt.2004.01.008 · Cited by 15
Skeletal muscle phenotypic switching in heart failure with preserved ejection fraction
Saw, E. L., Werner, L. D., Zamani, P. L., Chirinos, J. A., Valero‐Muñoz, M., & Sam, F. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.1016452 · Cited by 14
“While the mechanistic role of these mediators in SkM in HFpEF is unknown, chronic exposure to IL-6 has been shown to induce SkM atrophy (72, 73).”
Background
An Analysis of Differentially Expressed Coding and Long Non-Coding RNAs in Multiple Models of Skeletal Muscle Atrophy
Hitachi, K., Nakatani, M., Kiyofuji, Y., Inagaki, H., Kurahashi, H., & Tsuchida, K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052558 · Cited by 14
“These pathways include genes identified as negative (Cdkn1a and Ctsl) [25,26] and positive (Abcc8, Csrp3, Dlg5, Gdf5, Gpnmb, Il4ra, and Runx1) [27–34] regulators of muscle atrophy, supporting the validity of our analysis.”
Background
Breathlessness and inflammation: potential relationships and implications
Ryan, R., Spathis, A., Clow, A., & Booth, S. (2016) · Current Opinion in Supportive and Palliative Care · doi:10.1097/spc.0000000000000229 · Cited by 14
“Furthermore, anti-IL-6 receptor antibodies have been shown to reverse muscle wasting in IL-6 transgenic mice [46].”
Background
The regulation of sulphurated amino acid junctions: fact or fiction in the field of inflammation?
Santangelo, F. (2002) · Amino Acids · doi:10.1007/s00726-002-0206-y · Cited by 14

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)
ORCID: Tsujinaka, T
Suzuki, K
Tanaka, K
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 1996-01-01
Volume: 97
Issue: 1
Pages: 244-249
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci118398
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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Interleukin 6 receptor antibody inhibits muscle atrophy and modulates proteolytic systems in interleukin 6 transgenic mice.

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